Randomized Trial Comparing Sitagliptin to Placebo in Closed Loop
Condition: Diabetes Mellitus, Type 1
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1

Summary: 
      There are many recent advances in insulin treatment of type 1 Diabetes Mellitus (T1DM),
      however after a meal sugars are always a concern. There is a drug sitagliptin (Januvia) which
      is FDA approved to treat people with type 2 diabetes which helps correct their glucose
      (sugars) after meals. This study is going to test whether this drug can improve the after
      meal sugars in people with type 1 diabetes. To test this, you will be given a mixed meal and
      its effects on insulin levels. The hormones that affect blood glucose as well as your sugar
      levels will be measured by a series of blood tests. We will also look for high blood sugars
      which might occur because of food staying longer in the stomach than usual or due to the
      suppression of a hormone called glucagon which increases blood sugar. If you qualify, you
      will be given sitagliptin (Januvia) 50 mg and 100 mg dosages. You and the researchers will
      not know which dose you are taking at any single visit. We will first enroll 10 subjects with
      established type 1 Diabetes Mellitus for at least 1 year, between the ages of 18-30 years
      old. The first 10 patients will be evaluated for safety parameters such as ability to keep
      blood sugars < 70 mg/dl for at least 70% of the time, no episode of severe hypoglycemia (low
      blood sugars) and so on. After this safety criteria is established, we will then recruit
      subjects between the ages of 14-19 yrs for the next phase of the study. A total of 17
      subjects were enrolled into the study.
    

Detailed description: 
      Rationale: Sitagliptin has been extensively studied in patients with type 2 Diabetes Mellitus
      (T2DM). Sitagliptin increases endogenous GLP-1 (Glucagon like peptide) by inhibiting the
      break down of an enzyme DPP-4 (Dipeptidyl Peptidase 4). GLP-1 in turn results in glucagon
      suppression.This mechanism is very effective in improving after meal blood sugars, not only
      in type 2 diabetics but also in type 1 diabetes. In this study we will test the use of
      sitagliptin in decreasing after meal blood sugars in the setting of closed loop.Data Safety
      Monitoring Board (DSMB) will meet before the initiation of the study and before children are
      enrolled into the study. The safety data after the meeting will be submitted to the
      Institutional Review Board (IRB).

      Specific Aim: In the closed loop setting, to establish a safe and an effective dose of
      sitagliptin in type 1 diabetes (T1DM) compared to placebo and its effects in lowering the
      post meal glucose levels, Further to test its effects on insulin utilization , glucagon
      levels and gastric emptying.

      Hypothesis: Post meal sugars will decrease in a dose dependent manner due to glucagon
      suppression when sitagliptin is used in the closed loop setting as compared to placebo.

      Study Design: Following informed consent (and with appropriate subject assent), each subject
      with Type 1 DM will undergo 4 study visits: Screening , Part A (Placebo/Insulin) and Part B
      (Sitagliptin 100 mg). A randomized double-blinded 2-period cross over study trial will be
      used for the subjects to participate in the study . All the study subject's (18-30 yrs old)
      and the study staff (except one person) will be blinded to the study parts and they will do
      all the study Parts A and B in random order.

      Montefiore Medical Center (MMC) Investigational pharmacy and one of the study staff
      (excluding the PI) will be un-blinded to the protocol for doing the randomization table,
      dispensing, checking the dose of study medication and scheduling the study visits (done by
      the study staff person). The participants will be admitted to the Clinical Research Center
      (CRC) on two occasions for the Parts A and B following the screening visit. Parts A and B are
      done with at least 2 weeks apart.

      Inclusion/ Exclusion Criteria: Subjects with Type 1 DM in the age group of 14-35 years
      without any concomitant illnesses except treated hypothyroidism will be recruited and also
      have an HbA1C less than 8.5 %. Menstruating women must have a negative pregnancy test.
      Lactating and pregnant women will be excluded and anyone with anemia defined by Hemoglobin of
      less than 12 gm/dl. Also, subjects with a history of substance abuse (evaluated by medical
      history and CRAAFT questionnaire which will be administered at the screening visit) will be
      excluded. The subject's should not be on any other medication which affects blood sugars.

      Screening: After signing a consent form, a screening evaluation will be performed 4-6 weeks
      prior to study enrollment in the CRC. The evaluation will consist of medical history,
      physical examination (including height, weight, vital signs and tanner staging), and blood
      samples for clinical laboratory tests: CBC (complete blood count), Liver Function Tests
      (LFT's), amylase, lipase, creatinine and HemoglobinA1C (HbA1C). The approximate volume of
      blood drawn is expected to be 12 ml. CRAAFT questionnaire will be administered. Subjects will
      undergo a baseline blinded open loop evaluation using a Medtronic CGM iPro 2 (Continuous
      Glucose Monitoring System) which is the insertion device. It has three parts - a glucose
      sensor that is inserted subcutaneously, a transmitter which connects to the sensor electrode
      and is attached to the body and a receiver which displays the glucose values.

      Part A: The subjects will be admitted to the Clinical Research Center (CRC) around 2 PM on
      day 1. Vitals will be taken. IV will be placed and blood will be drawn to measure Stat CBC,
      HbA1C, Liver function tests, Serum Amylase, Serum Lipase and Serum Creatinine. Study will be
      continued only if their Hemoglobin is greater than 12 gm/ dl. Urine pregnancy test will be
      done for all female subjects prior to study. Insulin infusion through the subcutaneous pump
      will be continued or long acting analog, novolog will be given as per home regimen. Subjects
      will be on the continuous glucose monitoring system overnight till 9 PM on day 2.

      BLOOD SAMPLING AND MEDICATIONS: At 6.30 PM on day 1 subjects will be started on the
      closed-loop device for the automated delivery of insulin based on the glucose sensor
      measurements . The insulin dose will be based on the patient's usual insulin to carbohydrate
      ratio. Placebo pill will be given around 8 PM (0 min) and then dinner will be served as a
      carbohydrate consistent diet (60 gms of carbohydrate). Subjects will be on the closed loop
      device over night till 9 PM on day 2. On day 2 breakfast will be served at 7 AM (660 min) in
      the morning consisting of a boost (high protein drink) 9.6 oz, consumed over a period of
      10-15 min. Lunch and dinner will be served at 12 PM (960 min) and 5 PM (1260 min). At
      approximately 6.30 PM baseline blood samples will be drawn prior to study start for glucose,
      insulin, glucagon, GLP-1, DPP-4 activity and Sitagliptin. Also, there will be blood draws at
      the following time points: 0, 60, 120, 240, 360, 480, 540, 600, 660, 720, 780, 840, 900, 960,
      1020, 1080, 1140, 1200, 1260, 1320, 1380, 1440. The insulin pump basal rate (or novolog) will
      be set to continue as per home regimen. Blood glucose concentrations will be measured at the
      bedside using an Analox glucose analyzer. The subject will be discharged after this. They
      will not be paid separately for transportation, parking or child care. A social security
      number will be required. It will be kept confidential. For minors, compensation will be given
      to the parent, but it is intended for the child.

      A subject will be withdrawn from participating in the study if he/she meets any of the
      following conditions: 1) develops a chronic disease 2) develops anemia 3) becomes pregnant 4)
      develops a weight loss of greater than 10 pounds for unspecified reasons 5) loss of contact-
      if we are unable to reach a study subject (within 2 months of screening or completion of the
      first study) by phone or mail to schedule the next appointment. All study subjects (that are
      withdrawn from the study) will receive a phone call and a letter notifying them that they
      have been withdrawn. Blood samples will be kept for 20 years because some of the assays have
      not been developed for some of the hormone analyses. Since it is difficult to perform
      clinical studies in pediatrics, we feel it is better to bank blood samples and perform
      hormone analyses as newer assays become available rather than repeating the study.

      Part B: Will be identical as part A except that Sitagliptin 100 mg will be administered as a
      pill before dinner at 8 PM on day 1. In Part B urine pregnancy test will be done before the
      visit for all female subjects. Prior to each part, hemoglobin must be >12 g/dl and a female
      subject should test negative for pregnancy.

      Treatment of Hypoglycemia: If blood glucose values in a subject are less than 55 mg/dl, IV
      glucose of 5-10gm, or if blood glucose less than 50 mg/dl, 10-15 g will be administered for
      countering low blood glucose to achieve euglycemia (90-130 mg/dl). 1-2 doses of IV glucose
      should correct hypoglycemia. If more than 3-4 doses are required to achieve euglycemia, the
      study will be terminated and the subjects will be offered a meal tray and blood sugar
      rechecked to ensure euglycemia. After the completion of the first 2 study subjects, the data
      safety and monitoring committee will assess safety of the protocol, as well as drug doses and
      adjustments to the protocol will be made. If hypoglycemia occurs even with the reduced dose
      of insulin, further reduction in insulin dose will be advised. The total blood draw volume
      will be 95 cc (1/2 cup) for Part A and B.

      Statistical Analysis :

      Sample size: Data from an earlier trial determined that the mean area under the curve (AUC)
      for children with Type 1 DM with insulin alone was 470 mg*hr/dl. The current trial is
      designed to detect a 25% difference in mean area under curve (AUC) for glucose in the 1670
      min period. Based on power of 0.8, alpha of 0.05 and correlation coefficient of r >/= 0.5
      (based on previous studies) and standard deviation excursion measure AUC for glucose
      approximately 0.8 between two study conditions, we estimate a sample size of 16 subjects.
      With a usual 10% drop out rate noticed in our studies , we would need to recruit 17 subjects.

      Data Analysis: Two way analysis of variance (ANOVA) for repeated measures will be used to
      compare between the two study periods, insulin , glucagon and glucose concentrations over
      time. Mean area under the curve (AUC) over the time will be calculated and a modified paired
      t-test will be used for post hoc analysis.Differences will be considered significant at 0.05.
      Comparative and descriptive statistics will be computed using SPSS (Statistical Package for
      the Social Sciences) statistical software and Graph pad prism.
    

Intervention name(s): Placebo and Insulin monotherapy via CL; Sitagliptin and insulin/novolog via CL
Intervention type(s): Drug; Drug
Intervention description(s): In the control arm patient receives a placebo pill with the closed loop with insulin/novolog (placebo and insulin/novolog via CL); In the treatment arm the participant receives a single dose of sitagliptin with closed loop with insulin/novolog (Sitagliptin and insulin/novolog via CL), Part B
Other intervention name(s): Januvia
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Sitagliptin Phosphate; Insulin Aspart
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diabetes Mellitus, Type 1; Closed loop; Artificial Pancreas; Insulin; Sitagliptin; Januvia