Randomized Trial Comparing Sitagliptin to Placebo in Closed Loop

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.

Inclusion Criteria:

1. Age of 14 to 30 years

2. Subjects must be otherwise healthy except for T1DM, and treated for hypothyroidism if
present

3. Menstruating women must have negative pregnancy test.

4. Hemoglobin (Hb) more than 12 g/dl

Exclusion Criteria:

1. Having any other chronic condition except hypothyroidism stable on medications

2. On chronic medications that may affect glucose excursions

3. Hemoglobin less than 12 g/dl

4. Positive pregnancy test (based on Urine)

5. Pregnant or lactating mothers Known allergy to Januvia-