<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01722266</url>
  </required_header>
  <id_info>
    <org_study_id>NN1962</org_study_id>
    <nct_id>NCT01722266</nct_id>
  </id_info>
  <brief_title>Liraglutide in the Treatment of Type 1 Diabetes Mellitus</brief_title>
  <official_title>Liraglutide in the Treatment of Type 1 Diabetes Mellitus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University at Buffalo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novo Nordisk A/S</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University at Buffalo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypothesis 1: Treatment with Liraglutide in patients with type 1 diabetes decreases fasting,&#xD;
      postprandial and the overall mean glucose concentrations.&#xD;
&#xD;
      Aim 1.1: To compare the mean fasting, the mean weekly glucose and the standard deviation of&#xD;
      weekly blood glucose concentrations as recorded by continuous glucose monitoring prior to and&#xD;
      following 6 weeks and 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily. In&#xD;
      addition, the time spent at glucose concentrations &gt;150 and 200mg/dl and &lt;70 and &lt;40 mg/dl&#xD;
      will also be compared.&#xD;
&#xD;
      Aim 1.2: To compare the postprandial glucose concentrations following a test meal before and&#xD;
      after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily. Glucose&#xD;
      concentrations will be measured as areas under the curve for the data obtained from the meal&#xD;
      challenge.&#xD;
&#xD;
      Aim 1.3: To compare HbA1c levels(glycated hemoglobin) before and after 12 weeks of treatment&#xD;
      with 0.6, 1.2 and 1.8 mg of liraglutide daily Hypothesis 2: Treatment with Liraglutide in&#xD;
      patients with type 1 diabetes decreases postprandial glucagon concentrations and increases&#xD;
      postprandial C-peptide concentrations.&#xD;
&#xD;
      Aim 2.1: To compare fasting and postprandial glucagon and C-peptide concentrations following&#xD;
      a test meal before and after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide&#xD;
      daily.&#xD;
&#xD;
      Hypothesis 3: Treatment with Liraglutide in patients with type 1 diabetes delays gastric&#xD;
      emptying.&#xD;
&#xD;
      Aim 3.1: To compare the gastric emptying as measured by acetaminophen absorption before and&#xD;
      after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      RESEARCH DESIGN AND METHODS This investigation will be a prospective, randomized, double&#xD;
      blind, placebo controlled study conducted in type 1 diabetics. The study will be conducted at&#xD;
      Diabetes - Endocrinology Center of WNY at Millard Fillmore Hospital, affiliated to the State&#xD;
      University of New York at Buffalo.&#xD;
&#xD;
      Study Population: Seventy two patients with type 1 diabetes on treatment with either&#xD;
      continuous subcutaneous insulin infusion (CSII; also known as insulin pump) or multiple (four&#xD;
      or more) injections of insulin per day will be included in the study. They will be randomized&#xD;
      into 4 groups of 18 patients each. The patients will be randomized to placebo or 0.6 mg, 1.2&#xD;
      mg or 1.8 mg liraglutide daily. In view of the possibility of hypoglycemia and the side&#xD;
      effect of nausea all patients will be started on 0.6 mg of liraglutide per day. The dose will&#xD;
      then be titrated up to 1.2 and 1.8 mg on a weekly basis. No increases will be made once the&#xD;
      target dose has been achieved in each group. Subjects will be recruited from our own&#xD;
      patients, our existing database and from advertisements. The following insulin preparations&#xD;
      will be used in the study: insulin detemir, glargine, aspart, glulisine and lispro. Subjects&#xD;
      will continue to obtain their insulin supplies from their respective pharmacies.&#xD;
&#xD;
      STUDY DESIGN:&#xD;
&#xD;
      Screening Day (day -14):- Each patient will have completed the following procedures prior to&#xD;
      participating in the study.&#xD;
&#xD;
        1. Medical History;&#xD;
&#xD;
        2. Physical Exam;&#xD;
&#xD;
        3. Informed consent.&#xD;
&#xD;
        4. Baseline lab draw to measure Complete blood count, comprehensive metabolic panel, Hba1c&#xD;
           and lipid profile. All labs will be drawn in the fasting state in the morning before&#xD;
           10am.&#xD;
&#xD;
      Randomization Visit (day -7)&#xD;
&#xD;
      Randomization Method: After the screening visit, subjects who meet the inclusion and&#xD;
      exclusion criteria, will be assigned a number by a computerized random number generation&#xD;
      program (Microsoft office - Excel) and randomized to receive subcutaneous injection daily of&#xD;
      either Liraglutide 0.6mg (18 subjects), 1.2 mg (18 subjects), 1.8 mg (18 subjects) or placebo&#xD;
      (18 subjects) for 12 weeks. The subjects and the study coordinators will be blinded to the&#xD;
      treatment. The Liraglutide/placebo will be administered via a pen kit (obtained from Novo&#xD;
      Nordisk Pharmaceuticals). The dose will be given in the morning. The sponsor is providing&#xD;
      study medication in blinded form.&#xD;
&#xD;
      All subjects will be instructed by the study staff in the dosing and administration of the&#xD;
      study medication and will be seen by a Certified Diabetes Educator for instruction on&#xD;
      injection technique. All subjects will also be seen by a registered dietitian who will review&#xD;
      their carbohydrate counting and diet and make an assessment of their calorie and carbohydrate&#xD;
      intake. The subjects will be randomized but will not start the placebo or liraglutide&#xD;
      injection till study intervention visit 1.&#xD;
&#xD;
      All subjects will be advised to monitor their capillary blood glucose by fingerstick before&#xD;
      and 2 hours after each meal and to wear their CGM constantly for the duration of the study&#xD;
      The subjects will be asked to keep a diary of their food intake to measure their calorie&#xD;
      intake. For the entire duration of the study, the patients will maintain a diary to record&#xD;
      any hypoglycemia and other untoward side effects like nausea, changes in appetite and other&#xD;
      experiences. Patients will be instructed to call the Diabetes Center or an endocrinology&#xD;
      fellow directly in case of any problem or untoward side effects. They will be specifically&#xD;
      asked to call if they have hypoglycemia (blood sugar &lt;70 mg/dl) or hyperglycemia (blood sugar&#xD;
      &gt;250 mg/dl) on more than one occasion.&#xD;
&#xD;
      Study Intervention Visit 1 day 0:- Subjects will come fasting for this visit. Records of&#xD;
      blood glucose concentrations monitored by fingerstick and CGM for the previous 7 days will be&#xD;
      obtained to assess their glycemic control prior to liraglutide treatment. They will undergo a&#xD;
      meal challenge test (described below), Liraglutide or placebo injections at a dose of 0.6 mg&#xD;
      per day will then be started. No reduction will be made in the dose of pre-prandial insulin&#xD;
      boluses and basal insulin if A1C is greater than or equal to 7.5%. Subjects will decrease the&#xD;
      dose of pre-prandial insulin boluses by 25% and the basal by 25% if their A1C is less than or&#xD;
      equal to 7%. Subjects will decrease the dose of pre-prandial insulin boluses and basal&#xD;
      insulin by 10% if the A1C is between 7 and &amp; 7.5%. This reduction is based on our experience&#xD;
      (see preliminary data). Careful adjustments will be made to insulin doses at the discretion&#xD;
      of the investigators on the basis of the glucose data obtained from the patients. The target&#xD;
      blood glucose will be preprandial 90-120mg/dl and 2hour PP &lt; 140mg/dl, without increasing the&#xD;
      incidence of blood glucose &lt; 70mg/dl. Patients will return to the center after 7 days&#xD;
&#xD;
      Study Intervention Visit 2 day 7:- Blood glucose concentrations will be reviewed. Insulin&#xD;
      dose will be adjusted at the discretion of the study investigator to optimize blood sugar&#xD;
      control as per the targets mentioned above on day 0 visit. Patients will be advised to&#xD;
      increase the Liraglutide dose to 1.2 mg a day in those whose target dose is 1.2 or 1.8 mg.&#xD;
      They will return in 7 days.&#xD;
&#xD;
      Study Intervention Visit 3 day 14:- Blood glucose concentrations will be reviewed. Insulin&#xD;
      dose will be adjusted at the discretion of the study investigator to optimize blood sugar&#xD;
      control as per the targets mentioned above on day 0 visit. Patients with a target dose of 1.8&#xD;
      mg will be advised to increase the dose while others will continue on their previous dose.&#xD;
      They will return in 7 days.&#xD;
&#xD;
      Study Intervention Visit 4 day 21, Visit 5 day 28:&#xD;
&#xD;
      Records of blood glucose concentrations of the last 7 days will be collected. Insulin dose&#xD;
      will be adjusted at the discretion of the study investigator to optimize blood sugar control&#xD;
      as per the targets mentioned above on day 0 visit.&#xD;
&#xD;
      Study Intervention Visit 6 day 42, Visit 7 day 56, Visit 8 day 70:&#xD;
&#xD;
      Records of blood glucose concentrations of the last 15 days will be collected. Insulin dose&#xD;
      will be adjusted at the discretion of the study investigator to optimize blood sugar control&#xD;
      as per the targets mentioned above on day 0 visit.&#xD;
&#xD;
      Study Intervention Visit 9 day 84 Subjects will come fasting for this visit. Records of blood&#xD;
      glucose concentrations monitored by fingerstick or CGM for the previous 7 days will be&#xD;
      obtained to assess their glycemic control. They will undergo meal challenge test (described&#xD;
      below). After this visit, subjects will be discharged from the study.&#xD;
&#xD;
      Meal challenge test:- In order to assess the changes induced by liraglutide, a meal challenge&#xD;
      will be carried out prior to and following liraglutide (day 0 and day 84). (910 Calorie High&#xD;
      fat High carbohydrate meal as in several of our previous papers). Acetaminophen (1000 mg for&#xD;
      body weight &lt;70 kg or 1500 mg for body weight &gt;70 kg) will be ingested at the beginning of&#xD;
      the meal, and the blood levels of acetaminophen will be determined at intervals for&#xD;
      assessment of the rate of gastric emptying. Bolus Insulin will be injected immediately before&#xD;
      the meal based on the insulin carbohydrate ratio and correction factor for each individual&#xD;
      subject. Liraglutide will be injected only on day 84 (45 min prior to the meal). Sequential&#xD;
      blood samples will be obtained at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 and 300 min.&#xD;
      Samples at 15, 30, 45, 90, 150 and 210 min will be 5 ml while those at 0, 60, 120, 180, 240&#xD;
      and 300 min will be 30 ml (total volume=210 ml). Blood will be collected from an indwelling&#xD;
      intravenous canula in a superficial forearm vein.&#xD;
&#xD;
      Data safety and monitoring:&#xD;
&#xD;
      Timely, accurate, and complete reporting and analysis of safety information obtained from&#xD;
      clinical trials are crucial for the protection of subjects and investigators.&#xD;
&#xD;
      All subjects will be referred to liraglutide's labeling safety information, and will be&#xD;
      provided a copy of the package insert of the medication. Discussion of the potential side&#xD;
      effects and the different warning and precautions will take place at the time of signing the&#xD;
      informed consent.&#xD;
&#xD;
      The following Information from the boxed warning in the package insert regarding the risk of&#xD;
      thyroid c-cell tumors will be discussed in details with all participating subjects&#xD;
      &quot;Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at&#xD;
      clinically relevant exposures in both genders of rats and mice. It is unknown whether&#xD;
      Liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in&#xD;
      humans, as human relevance could not be ruled out by clinical or nonclinical studies.&#xD;
      Liraglutide is contraindicated in patients with a personal or family history of MTC and in&#xD;
      patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in&#xD;
      rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical&#xD;
      trials, but this may have increased the number of unnecessary thyroid surgeries. It is&#xD;
      unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human&#xD;
      risk of thyroid C-cell tumors.&quot;&#xD;
&#xD;
      In addition, the following FDA text regarding the risk of developing fibrosarcomas will be&#xD;
      discussed with all participating subjects &quot;In a 2-year repeat subcutaneous dose&#xD;
      carcinogenicity study of liraglutide injected once a day in CD-1 mice, a treatment-related&#xD;
      increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for&#xD;
      drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the&#xD;
      high local concentration of drug near the injection site. The liraglutide concentration in&#xD;
      the clinical formulation (6 mg/mL) is 10 times higher than the concentration in the&#xD;
      formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study&#xD;
      (0.6 mg/mL)&quot;.&#xD;
&#xD;
      All Adverse events(AEs) will be reported at the time of the visit or by telephone when it&#xD;
      occurs. Those meeting the definition of Serious Adverse Events(SAE's) must be reported using&#xD;
      the SAE Form. Medical events that occur between the signing of the Informed Consent and the&#xD;
      first intake of study drug will be documented in the medical history. Subjects should&#xD;
      voluntarily report any AEs or in response to general, non-directed questioning. For each AE&#xD;
      volunteered by the subject, the investigator will obtain all the information required to&#xD;
      complete the AE page of the Case Report Form(CRF), in accordance with the guidelines that&#xD;
      accompany it.&#xD;
&#xD;
      All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, will&#xD;
      be recorded using medical terminology in the source document and on the CRF. Whenever&#xD;
      possible, diagnoses will be given when signs and symptoms are due to a common etiology (e.g.,&#xD;
      cough, runny nose, sneezing, sore throat, and head congestion should be reported as &quot;upper&#xD;
      respiratory infection). Investigators will record on the CRF their opinion concerning the&#xD;
      relationship of the AE to study therapy. All measures required for AE management will be&#xD;
      recorded in the source document and reported according to sponsor instructions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">April 2014</completion_date>
  <primary_completion_date type="Actual">April 2014</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Mean Weekly Glucose Concentrations From Baseline at 12 Weeks</measure>
    <time_frame>12 Weeks</time_frame>
    <description>The primary endpoint of the study is to detect a difference from baseline in mean weekly blood glucose concentrations before and after 12 weeks of treatment in each of the Liraglutide groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in HbA1c From Baseline at 12 Weeks</measure>
    <time_frame>Baseline and 12 Weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Body Weight From Baseline at Week 12</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Total Insulin Dose From Baseline at 12 Weeks</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Total insulin dose = Basal insulin dose plus bolus insulin dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in the Area Under Curve(AUC) of Glucose Following the Meal</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Acetaminophen Concentrations Following Meal Challenge</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Carbohydrate Intake</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin, C-peptide, Glucagon, GLP-1(Glucagon Like Peptide-1) and GIP(Gastric Inhibitory Polypeptide) Concentrations Following Meal Challenge.</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">72</enrollment>
  <condition>Type 1 Diabetes</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Daily Injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Liraglutide 1.8mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Daily Injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Liraglutide 1.2mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Daily injections</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Liraglutide 0.6 mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Daily injection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liraglutide</intervention_name>
    <description>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.&#xD;
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.</description>
    <arm_group_label>Liraglutide 0.6 mg</arm_group_label>
    <arm_group_label>Liraglutide 1.2mg</arm_group_label>
    <arm_group_label>Liraglutide 1.8mg</arm_group_label>
    <other_name>Victoza</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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.&#xD;
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.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with type 1 diabetes mellitus: Fasting c-peptide &lt; 0.1nmol/l on insulin&#xD;
             therapy for more than 12 months with or without history of diabetic ketoacidosis.&#xD;
&#xD;
          2. Using a continuous glucose monitoring device (CGM) and regularly measuring their blood&#xD;
             sugars four times daily&#xD;
&#xD;
          3. HbA1c of less than 8.5%.&#xD;
&#xD;
          4. Well versed with carbohydrate counting&#xD;
&#xD;
          5. Age 18-75 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Type 1 diabetes for less than 12 months;&#xD;
&#xD;
          2. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery&#xD;
             bypass, surgery or coronary angioplasty) in the previous four weeks;&#xD;
&#xD;
          3. Hepatic disease (transaminase &gt; 3 times normal) or cirrhosis;&#xD;
&#xD;
          4. Renal impairment (serum creatinine &gt; 1.5);&#xD;
&#xD;
          5. HIV or Hepatitis C positive status;&#xD;
&#xD;
          6. Participation in any other concurrent clinical trial;&#xD;
&#xD;
          7. Any other life-threatening, non-cardiac disease;&#xD;
&#xD;
          8. Use of an investigational agent or therapeutic regimen within 30 days of study.&#xD;
&#xD;
          9. history of pancreatitis&#xD;
&#xD;
         10. pregnancy&#xD;
&#xD;
         11. inability to give informed consent&#xD;
&#xD;
         12. history of gastroparesis&#xD;
&#xD;
         13. history of medullary thyroid carcinoma or MEN 2 syndrome.&#xD;
&#xD;
         14. Family history of MEN 2, Family history of medullary thyroid cancer, or familial&#xD;
             medullary thyroid cancer&#xD;
&#xD;
         15. Women of childbearing potential who are not using adequate contraception 16) Women who&#xD;
             are pregnant&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paresh Dandona, MBBS, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kaleida Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Diabetes-Endocrinology Center of Western NY</name>
      <address>
        <city>Williamsville</city>
        <state>New York</state>
        <zip>14221</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Kuhadiya ND, Malik R, Bellini NJ, Patterson JL, Traina A, Makdissi A, Dandona P. Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. Endocr Pract. 2013 Nov-Dec;19(6):963-7. doi: 10.4158/EP13065.OR.</citation>
    <PMID>23807520</PMID>
  </reference>
  <reference>
    <citation>Varanasi A, Bellini N, Rawal D, Vora M, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol. 2011 Jul;165(1):77-84. doi: 10.1530/EJE-11-0330. Epub 2011 Jun 6.</citation>
    <PMID>21646283</PMID>
  </reference>
  <reference>
    <citation>Kielgast U, Asmar M, Madsbad S, Holst JJ. Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients. J Clin Endocrinol Metab. 2010 May;95(5):2492-6. doi: 10.1210/jc.2009-2440. Epub 2010 Mar 5.</citation>
    <PMID>20207828</PMID>
  </reference>
  <reference>
    <citation>Rother KI, Spain LM, Wesley RA, Digon BJ 3rd, Baron A, Chen K, Nelson P, Dosch HM, Palmer JP, Brooks-Worrell B, Ring M, Harlan DM. Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care. 2009 Dec;32(12):2251-7. doi: 10.2337/dc09-0773. Epub 2009 Oct 6.</citation>
    <PMID>19808924</PMID>
  </reference>
  <reference>
    <citation>Ghanim H, Aljada A, Daoud N, Deopurkar R, Chaudhuri A, Dandona P. Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects. Diabetologia. 2007 Feb;50(2):278-85. doi: 10.1007/s00125-006-0508-9. Epub 2006 Dec 16.</citation>
    <PMID>17180352</PMID>
  </reference>
  <reference>
    <citation>Wajchenberg BL, Feitosa AC, Rassi N, Lerario AC, Betti RT. Glycemia and cardiovascular disease in type 1 diabetes mellitus. Endocr Pract. 2008 Oct;14(7):912-23. doi: 10.4158/EP.14.7.912.</citation>
    <PMID>18996824</PMID>
  </reference>
  <reference>
    <citation>Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Maggs DG, Wintle ME. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007 Jan;29(1):139-53. doi: 10.1016/j.clinthera.2007.01.015.</citation>
    <PMID>17379054</PMID>
  </reference>
  <reference>
    <citation>Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther. 2009 Nov;31(11):2472-88. doi: 10.1016/j.clinthera.2009.11.034.</citation>
    <PMID>20109994</PMID>
  </reference>
  <reference>
    <citation>Varanasi A, Patel P, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Clinical use of liraglutide in type 2 diabetes and its effects on cardiovascular risk factors. Endocr Pract. 2012 Mar-Apr;18(2):140-5. doi: 10.4158/EP11169.OR.</citation>
    <PMID>21856595</PMID>
  </reference>
  <reference>
    <citation>Varanasi A, Chaudhuri A, Dhindsa S, Arora A, Lohano T, Vora MR, Dandona P. Durability of effects of exenatide treatment on glycemic control, body weight, systolic blood pressure, C-reactive protein, and triglyceride concentrations. Endocr Pract. 2011 Mar-Apr;17(2):192-200. doi: 10.4158/EP10199.OR.</citation>
    <PMID>20841306</PMID>
  </reference>
  <reference>
    <citation>Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens. 2010 Mar;23(3):334-9. doi: 10.1038/ajh.2009.245. Epub 2009 Dec 17.</citation>
    <PMID>20019672</PMID>
  </reference>
  <reference>
    <citation>Lebovitz HE. Adjunct therapy for type 1 diabetes mellitus. Nat Rev Endocrinol. 2010 Jun;6(6):326-34. doi: 10.1038/nrendo.2010.49. Epub 2010 Apr 20.</citation>
    <PMID>20404854</PMID>
  </reference>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>November 2, 2012</study_first_submitted>
  <study_first_submitted_qc>November 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 6, 2012</study_first_posted>
  <results_first_submitted>February 9, 2015</results_first_submitted>
  <results_first_submitted_qc>March 2, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">March 13, 2015</results_first_posted>
  <last_update_submitted>September 15, 2022</last_update_submitted>
  <last_update_submitted_qc>September 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Kaleida Health</investigator_affiliation>
    <investigator_full_name>Paresh Dandona</investigator_full_name>
    <investigator_title>Distinguished Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Liraglutide</keyword>
  <keyword>Glucagon</keyword>
  <keyword>Systolic blood pressure</keyword>
  <keyword>Weight</keyword>
  <keyword>Carbohydrate intake</keyword>
  <keyword>Insulin dose</keyword>
  <keyword>HbA1c</keyword>
  <keyword>Post-prandial glucagon</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liraglutide</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
        </group>
        <group group_id="P2">
          <title>Liraglutide 1.8mg</title>
          <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
        <group group_id="P3">
          <title>Liraglutide 1.2mg</title>
          <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
        <group group_id="P4">
          <title>Liraglutide 0.6 mg</title>
          <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="18"/>
                <participants group_id="P3" count="18"/>
                <participants group_id="P4" count="18">3 withdrew consent; 1 dropped out due to nausea</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="15"/>
                <participants group_id="P3" count="13"/>
                <participants group_id="P4" count="18">3 subjects randomized to 1.2 mg group and 1 to 1.8 mg group tolerated only 0.6 mg</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="5"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Tolerated only 0.6 mg liraglutide</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Dropped out due to Nausea</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
        </group>
        <group group_id="B2">
          <title>Liraglutide 1.8mg</title>
          <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
        <group group_id="B3">
          <title>Liraglutide 1.2mg</title>
          <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
        <group group_id="B4">
          <title>Liraglutide 0.6 mg</title>
          <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="17"/>
            <count group_id="B2" value="15"/>
            <count group_id="B3" value="13"/>
            <count group_id="B4" value="18"/>
            <count group_id="B5" value="63"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50" spread="3"/>
                    <measurement group_id="B2" value="42" spread="3"/>
                    <measurement group_id="B3" value="42" spread="3"/>
                    <measurement group_id="B4" value="45" spread="4"/>
                    <measurement group_id="B5" value="44" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="9"/>
                    <measurement group_id="B5" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="9"/>
                    <measurement group_id="B5" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="17"/>
                    <measurement group_id="B5" value="59"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="18"/>
                    <measurement group_id="B5" value="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age of Type 1 Diabetes Diagnosis</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19" spread="3"/>
                    <measurement group_id="B2" value="21" spread="3"/>
                    <measurement group_id="B3" value="21" spread="3"/>
                    <measurement group_id="B4" value="19" spread="3"/>
                    <measurement group_id="B5" value="20" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Mean Weekly Glucose Concentrations From Baseline at 12 Weeks</title>
        <description>The primary endpoint of the study is to detect a difference from baseline in mean weekly blood glucose concentrations before and after 12 weeks of treatment in each of the Liraglutide groups.</description>
        <time_frame>12 Weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Liraglutide 1.8mg</title>
            <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>Liraglutide 1.2mg</title>
            <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Liraglutide 0.6 mg</title>
            <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Weekly Glucose Concentrations From Baseline at 12 Weeks</title>
          <description>The primary endpoint of the study is to detect a difference from baseline in mean weekly blood glucose concentrations before and after 12 weeks of treatment in each of the Liraglutide groups.</description>
          <units>mg/dl</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1" spread="0"/>
                    <measurement group_id="O2" value="-10" spread="1"/>
                    <measurement group_id="O3" value="-10" spread="2"/>
                    <measurement group_id="O4" value="-0.3" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in HbA1c From Baseline at 12 Weeks</title>
        <time_frame>Baseline and 12 Weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Liraglutide 1.8mg</title>
            <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>Liraglutide 1.2mg</title>
            <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Liraglutide 0.6 mg</title>
            <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in HbA1c From Baseline at 12 Weeks</title>
          <units>Percent</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.30" spread="0.15"/>
                    <measurement group_id="O2" value="-0.42" spread="0.15"/>
                    <measurement group_id="O3" value="-0.78" spread="0.15"/>
                    <measurement group_id="O4" value="-0.26" spread="0.17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Body Weight From Baseline at Week 12</title>
        <time_frame>Baseline and 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Liraglutide 1.8mg</title>
            <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>Liraglutide 1.2mg</title>
            <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Liraglutide 0.6 mg</title>
            <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Body Weight From Baseline at Week 12</title>
          <units>Kg</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.3" spread="0.5"/>
                    <measurement group_id="O2" value="-4.8" spread="0.7"/>
                    <measurement group_id="O3" value="-5.0" spread="1.2"/>
                    <measurement group_id="O4" value="-2.7" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Total Insulin Dose From Baseline at 12 Weeks</title>
        <description>Total insulin dose = Basal insulin dose plus bolus insulin dose.</description>
        <time_frame>Baseline and 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Liraglutide 1.8mg</title>
            <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>Liraglutide 1.2mg</title>
            <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Liraglutide 0.6 mg</title>
            <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Total Insulin Dose From Baseline at 12 Weeks</title>
          <description>Total insulin dose = Basal insulin dose plus bolus insulin dose.</description>
          <units>Units</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.4" spread="0.7"/>
                    <measurement group_id="O2" value="-10" spread="0.5"/>
                    <measurement group_id="O3" value="-12.1" spread="0.7"/>
                    <measurement group_id="O4" value="-2.8" spread="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Reduction in the Area Under Curve(AUC) of Glucose Following the Meal</title>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Serum Acetaminophen Concentrations Following Meal Challenge</title>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Carbohydrate Intake</title>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Liraglutide 1.8mg</title>
            <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>Liraglutide 1.2mg</title>
            <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Liraglutide 0.6 mg</title>
            <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Carbohydrate Intake</title>
          <units>grams</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-13.4" spread="2.6"/>
                    <measurement group_id="O2" value="-46.4" spread="1.6"/>
                    <measurement group_id="O3" value="-47.6" spread="2.6"/>
                    <measurement group_id="O4" value="-23.7" spread="2.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Insulin, C-peptide, Glucagon, GLP-1(Glucagon Like Peptide-1) and GIP(Gastric Inhibitory Polypeptide) Concentrations Following Meal Challenge.</title>
        <time_frame>12 weeks</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 weeks.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Daily Injection&#xD;
Placebo: 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.&#xD;
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.</description>
        </group>
        <group group_id="E2">
          <title>Liraglutide 1.8mg</title>
          <description>Daily Injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
        <group group_id="E3">
          <title>Liraglutide 1.2mg</title>
          <description>Daily injections&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
        <group group_id="E4">
          <title>Liraglutide 0.6 mg</title>
          <description>Daily injection&#xD;
Liraglutide: 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.&#xD;
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.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="11" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Transient Nausea</sub_title>
                <description>Transient nausea reported at the time of initiation of liraglutide for first 2-5 days and then another 2-4 days at the time of escalation of the dose. Nausea is a common side effect of liralgutide.</description>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="15"/>
                <counts group_id="E3" events="10" subjects_affected="10" subjects_at_risk="13"/>
                <counts group_id="E4" events="11" subjects_affected="11" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Three subjects randomized to 1.2 mg group and one subject randomized to 1.8 mg group tolerated only 0.6 mg. These 4 subjects were included in the 0.6 mg group for analysis.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Nitesh D Kuhadiya,MD,MPH ;Co-Investigator;Assistant Professor of Medicine, Section of Endocrinology</name_or_title>
      <organization>University at Buffalo</organization>
      <phone>716-626-7998</phone>
      <email>niteshku@buffalo.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01722266
org study id: NN1962
nct id: NCT01722266
lead sponsor: 
collaborator: 
has dmc: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Change in Mean Weekly Glucose Concentrations From Baseline at 12 Weeks
time frame: 12 Weeks
description: The primary endpoint of the study is to detect a difference from baseline in mean weekly blood glucose concentrations before and after 12 weeks of treatment in each of the Liraglutide groups.
measure: Change in HbA1c From Baseline at 12 Weeks
time frame: Baseline and 12 Weeks
measure: Change in Body Weight From Baseline at Week 12
time frame: Baseline and 12 weeks
measure: Change in Total Insulin Dose From Baseline at 12 Weeks
time frame: Baseline and 12 weeks
description: Total insulin dose = Basal insulin dose plus bolus insulin dose.
measure: Reduction in the Area Under Curve(AUC) of Glucose Following the Meal
time frame: 12 weeks
measure: Serum Acetaminophen Concentrations Following Meal Challenge
time frame: 12 weeks
measure: Carbohydrate Intake
time frame: 12 weeks
measure: Insulin, C-peptide, Glucagon, GLP-1(Glucagon Like Peptide-1) and GIP(Gastric Inhibitory Polypeptide) Concentrations Following Meal Challenge.
time frame: 12 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Daily Injection
arm group label: Liraglutide 1.8mg
arm group type: Active Comparator
description: Daily Injection
arm group label: Liraglutide 1.2mg
arm group type: Active Comparator
description: Daily injections
arm group label: Liraglutide 0.6 mg
arm group type: Active Comparator
description: Daily injection
intervention type: Drug
intervention name: Liraglutide
description: 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.
arm group label: Liraglutide 0.6 mg
arm group label: Liraglutide 1.2mg
arm group label: Liraglutide 1.8mg
other name: Victoza
intervention type: Drug
intervention name: Placebo
description: 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.
arm group label: Placebo
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Paresh Dandona, MBBS, PhD
role: Principal Investigator
affiliation: Kaleida Health
facility: 
country: United States
citation: Kuhadiya ND, Malik R, Bellini NJ, Patterson JL, Traina A, Makdissi A, Dandona P. Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. Endocr Pract. 2013 Nov-Dec;19(6):963-7. doi: 10.4158/EP13065.OR.
PMID: 23807520
citation: Varanasi A, Bellini N, Rawal D, Vora M, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol. 2011 Jul;165(1):77-84. doi: 10.1530/EJE-11-0330. Epub 2011 Jun 6.
PMID: 21646283
citation: Kielgast U, Asmar M, Madsbad S, Holst JJ. Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients. J Clin Endocrinol Metab. 2010 May;95(5):2492-6. doi: 10.1210/jc.2009-2440. Epub 2010 Mar 5.
PMID: 20207828
citation: Rother KI, Spain LM, Wesley RA, Digon BJ 3rd, Baron A, Chen K, Nelson P, Dosch HM, Palmer JP, Brooks-Worrell B, Ring M, Harlan DM. Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care. 2009 Dec;32(12):2251-7. doi: 10.2337/dc09-0773. Epub 2009 Oct 6.
PMID: 19808924
citation: Ghanim H, Aljada A, Daoud N, Deopurkar R, Chaudhuri A, Dandona P. Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects. Diabetologia. 2007 Feb;50(2):278-85. doi: 10.1007/s00125-006-0508-9. Epub 2006 Dec 16.
PMID: 17180352
citation: Wajchenberg BL, Feitosa AC, Rassi N, Lerario AC, Betti RT. Glycemia and cardiovascular disease in type 1 diabetes mellitus. Endocr Pract. 2008 Oct;14(7):912-23. doi: 10.4158/EP.14.7.912.
PMID: 18996824
citation: Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Maggs DG, Wintle ME. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007 Jan;29(1):139-53. doi: 10.1016/j.clinthera.2007.01.015.
PMID: 17379054
citation: Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther. 2009 Nov;31(11):2472-88. doi: 10.1016/j.clinthera.2009.11.034.
PMID: 20109994
citation: Varanasi A, Patel P, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Clinical use of liraglutide in type 2 diabetes and its effects on cardiovascular risk factors. Endocr Pract. 2012 Mar-Apr;18(2):140-5. doi: 10.4158/EP11169.OR.
PMID: 21856595
citation: Varanasi A, Chaudhuri A, Dhindsa S, Arora A, Lohano T, Vora MR, Dandona P. Durability of effects of exenatide treatment on glycemic control, body weight, systolic blood pressure, C-reactive protein, and triglyceride concentrations. Endocr Pract. 2011 Mar-Apr;17(2):192-200. doi: 10.4158/EP10199.OR.
PMID: 20841306
citation: Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens. 2010 Mar;23(3):334-9. doi: 10.1038/ajh.2009.245. Epub 2009 Dec 17.
PMID: 20019672
citation: Lebovitz HE. Adjunct therapy for type 1 diabetes mellitus. Nat Rev Endocrinol. 2010 Jun;6(6):326-34. doi: 10.1038/nrendo.2010.49. Epub 2010 Apr 20.
PMID: 20404854
responsible party type: Principal Investigator
investigator affiliation: Kaleida Health
investigator full name: Paresh Dandona
investigator title: Distinguished Professor of Medicine
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Liraglutide
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Three subjects randomized to 1.2 mg group and one subject randomized to 1.8 mg group tolerated only 0.6 mg. These 4 subjects were included in the 0.6 mg group for analysis.
point of contact: 