Clinical trial NCT01269034
Conditions: Type 1 Diabetes
Keywords: Type 1 diabetes Milletus diabetes healthy controls exenatide byetta
Sponsor: Albert Einstein College of Medicine
Start date: 2010-12-01; Completion date: 2017-01-31
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
There are many recent advances in insulin treatment of type 1 diabetes, however after a meal sugars are always a concern. There is a drug Exenatide (Byetta) which is FDA approved to treat people with type 2 diabetes which helps correct their glucoses (sugars) after meals. This study is going to test whether this drug can improve the after meal sugars in people with new onset type 1 diabetes. To test this you will be given a dose of exenatide (1.25 mcg) and long acting insulin or inulin alone before the boost. There is also a placebo group (healthy subjects) who do not get any medication before the boost. Insulin levels and other hormones that affect blood glucose as well as your sugar will be measured by a series of blood tests. The role exenatide as compared to insulin alone will be examined to prevent low 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 exenatide (Byetta 1.25 mcg) along with insulin or insulin alone. You and the researchers will not know which dose you are taking at any single visit. A total of 20 people in which some will be children aged 12- 18 years will participate, being diagnosed within 3 months of having been found to have type 1 diabetes.

Detailed description:
The specific aims of this study are to determine the following:

1. The role of exenatide as compared to insulin monotherapy in reducing postprandial hyperglycemia.
2. The role of exenatide on postprandial glucagon and gastric emptying.
3. The effect of long acting insulin on postprandial glucose excursions, glucagon concentrations and gastric emptying.
4. Postprandial glucose excursions, glucagon concentrations and gastric emptying in normal healthy controls.

Study Design:

A randomized, non-blinded trial with a crossover design will be used. Following informed consent and with appropriate subject assent, all subjects will have a screening visit. Following the screening visit, subjects with T1DM will undergo 3 studies: Part A (exenatide and long acting insulin), Part B (rapid and long acting insulin) and Part C (long acting insulin only). The subjects will be admitted to the CRC on three separate occasions, at least 3-4 weeks apart. The three studies will be performed in a random order and the randomization will be done using a computerized system. The healthy controls will undergo a single study visit. Except for the absence of diabetes, the healthy controls will be identical to the study subjects. Subjects with new onset diabetes will be compared to healthy controls.

During the study, if blood glucose values in a subject are less than 55 mg/dl, IV glucose of 5-15 grams will be administered to achieve euglycemia (90-130 mg/dl). 1-2 doses of IV glucose should correct hypoglycemia. If more than 3 doses are required to achieve euglycemia, the study will be terminated, the subject will be offered a meal tray and blood sugar rechecked to ensure euglycemia. If blood sugar at any time is more than 350 with moderate ketones, the study will be terminated.

At around 1 PM (270 min), lunch will be provided (consistent carbohydrate meal) and insulin will be given as per the subject's prescribed regimen. The subject will be discharged home with a designated driver due to the risk of hypoglycemia.

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 the investigators 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.

Arms: arm 1: Exenatide and long acting insulin before the boost. arm 2: Rapid and long acting insulin before the boost arm 3: long acting insulin+ rapid acting+1.25 mcg Exenatide before the boost arm 4: healthy controls without any medication before the boost.
Interventions: intervention 1: Exenatide intervention 2: Rapid and long acting insulin intervention 3: long acting insulin + rapid acting + 1.25 mcg Exenatide
Intervention descriptions: intervention 1: 1.25 mcg before the boost sub-cutaneously. intervention 2: Depends on their Carbohydrate ratio and body needs intervention 3: Depends on their body needs.

Protocol documents:
Prot_000.pdf: 
Background: 
Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases of childhood. In 
the US, it accounts for about two thirds of newly diagnosed diabetes in patients less than 19 
years of age. It is caused by the autoimmune destruction of beta cells in the pancreas resulting in 
insulin deficiency. The Diabetes Control and Complications Trial demonstrated that improved 
glycemic control prevents and/or delays long-term complications associated with T1DM. 
Improved outcomes in glycemic control have been seen in recent years with new insulin analogs 
and delivery devices. However, blood glucose control still remains imperfect and quality of life 
is affected by the continued dependence on insulin. Hence, the long term goal is to maintain beta 
cell mass in the pancreas. Higher residual beta cell mass early in the disease will result in long 
term benefits. To achieve this, various therapeutic trials have included therapies such as 
immunosuppression, immunomodulation, antigen specific therapy, islet cell transplant and stem 
cell transplant. However, these therapies have severe complications requiring further 
development. Therefore, until such therapies are available, other agents that have received FDA 
approval must be explored to improve glycemic control. Exenatide, a GLP-1 agonist, is one such 
agent that is approved for use in adults with type 2 diabetes mellitus (T2DM). Glucagon like 
peptide-1 (GLP-1) is secreted from the entero-endocrine cells following nutrient ingestion. It 
regulates glucose metabolism through its effects on the pancreatic islet cells, the gastrointestinal 
tract, and the central nervous system. The principal mechanisms include stimulation of insulin 
secretion, inhibition of glucagon secretion, delay in gastric emptying and reduction in food 
intake. In addition, GLP-1 has been shown to be important in beta cell proliferation and survival. 
In animal studies, GLP-1 is associated with induction of pancreatic duodenal homeobox 1 (pdx1) 
gene expression. Pdx1 is a transcription factor, which is primarily expressed in the endocrine 
pancreas and subsets of entero-endocrine cells in the duodenum. It is highly conserved among 
different species. Genetic disruptions of the pdx1 gene in mice abrogate normal pancreatic 
development and formation. In humans, inactivating mutations of the pdx1 gene is associated 
with pancreatic agenesis. Hence pdx1 is critical for pancreatic development and formation. GLP-
1 actions may be mediated through pdx1 and thus influence beta cell proliferation and survival. 
Furthermore, GLP-1 regulates a subset of genes including pro-insulin, GLUT-2 and glucokinase 
that are known transcriptional targets of pdx1 action. GLP-1 has anti-apoptotic properties 
independent of its action on glucose regulation and islet proliferation. Apoptosis related cell 
IRB NUMBER: 2010-435
IRB APPROVAL DATE: 04/27/2015
Title: New Onset Type 1 Diabetes: Role of Exenatide 


death is a feature of both type 1 and type 2 diabetes mellitus. In mice, with streptozotocin-
induced diabetes, there is increased apoptotic related cell death. In these mice, treatment with 
exendin-4, a GLP-1 receptor analog, resulted in euglycemia significantly longer than those that 
were not treated with GLP-1. Conversely, mice with targeted disruption of the GLP-1 receptor 
gene exhibited increased apoptosis after streptozotocin administration. Furthermore, exendin-4 
directly reduced cytokine-induced apoptosis in purified rat beta cells exposed to a host of 
cytokines such as interleukin 1a, tumor necrosis factor alpha, and interferon in vitro. Exenatide is 
a synthetic analog of exendin-4. It has properties similar to GLP-1 but has only fifty percent 
homology to native GLP-1. The investigator’s brochure for exenatide suggests that in adults with 
T2DM, it was well tolerated at 0.1mcg/kg/dose and resulted in glucose lowering. GLP-1 is 
metabolized by di-peptidyl peptidases (DPP-IV) proteolysis and clearance occurs via the 
kidneys. However, in vitro studies with human placental DPP-IV demonstrated that exenatide is 
resistant to degradation by this enzyme. No evidence of plasma accumulation with multiple 
doses was noted in adults with renal dysfunction. Rodent models of hepatic disease with reduced 
liver function (thioacetamide-and D-galactosamine-induced liver injury) demonstrated no change 
in the pK role of the liver in the metabolism/ elimination of exenatide, suggesting that the liver 
does not play a major role in exenatide clearance. Adult studies demonstrate a dose-proportional 
Cmax and AUC in the 5-10 microgram dose range. The drug is rapidly absorbed with a Tmax of 
approximately 1-3 hours; mean Cmax values of 0.88-0.99 pmol/L (dose range 5-10 ìgm), and T½ 
beta of 2-4 hours. Bioavailability of exenatide was comparable whether injected subcutaneously 
in the arm, thigh, or abdomen. Exenatide has been extensively studied in patients with T2DM. 
Clinical studies indicate that exenatide is very effective in decreasing postprandial glucose 
excursions. Limited studies of GLP-1 infusions are reported in adults with T1DM. The principal 
mechanism of action is increased insulin release from the pancreatic islets, suppression of 
glucagon leading to decreased hepatic glucose production and decreased immediate postprandial 
hyperglycemia. In addition, exenatide delays gastric emptying and decreases food intake through 
centrally mediated mechanisms causing satiety and improved weight control. These effects result 
in the benefit of further reduction of Hemoglobin A1C (HgbA1C) beyond the reduction observed 
with insulin alone. Children and adolescents with new onset T1DM demonstrate marked increase 
in postprandial glucose concentrations despite the use of intense insulin therapy. Use of 
exenatide would be a novel way to reduce postprandial hyperglycemia and perhaps preserve beta 
IRB NUMBER: 2010-435
IRB APPROVAL DATE: 04/27/2015


cell mass in the pancreas. Our hypothesis is that exenatide can reduce postprandial glycemic 
excursions by twenty percent compared to insulin mono-therapy in children and adolescents with 
new onset type 1 diabetes. In addition, we would like to study the safety of this low dose of 
Exenatide (1.25 micrograms) in new onset type 1 diabetes. The specific aims of this study are to 
determine the following: 1. The role of exenatide as compared to insulin mono-therapy in 
reducing postprandial hyperglycemia. 2. The role of exenatide on postprandial glucagon and 
gastric emptying. 3. The effect of long acting insulin/ rapid acting insulin on a basal rate in an 
insulin pump on postprandial glucose excursions, glucagon concentrations and gastric emptying. 
4. Postprandial glucose excursions, glucagon concentrations and gastric emptying in normal
healthy controls. 
Study Design: 
 A randomized, non-blinded trial with a crossover design will be used. Following informed 
consent and with appropriate subject assent, all subjects will have a screening visit. Following 
the screening visit, subjects with T1DM will undergo 3 studies: Part A (exenatide and long 
acting insulin), Part B (rapid and long acting insulin) and Part C (long acting insulin + rapid 
acting insulin + exenatide). For Type 1 diabetes subjects who are on an insulin pump, for Part A 
they will be on their usual basal rate of rapid acting insulin and they would receive exenatide, for 
Part B they will be on their usual basal rate of rapid acting insulin and before they drink the 
boost milk shake, they will receive an insulin bolus according to their carbohydrate and 
sensitivity ratio's. For Part C they will be on their usual basal rate of rapid acting insulin and will 
also get exenatide and bolus of rapid acting insulin before they drink the boost milkshake.The 
subjects will be admitted to the CRC on three separate occasions, at least 3-4 weeks apart. The 
three studies will be performed in a random order and the randomization will be done using a 
computerized system. The healthy controls will undergo a single study visit and will not receive 
any insulin or study drug. Except for the absence of diabetes, the healthy controls will be 
identical to the study subjects. Subjects with new onset diabetes will be compared to healthy 
controls. Inclusion Criteria: 1. Age between 12-18 years of age at the time of enrollment. 2. 
Diagnosed with antibody positive T1DM in the past 3 months. 3. Otherwise healthy except for 
their TIDM and treated hypothyroidism. 4. Females must have a negative pregnancy test. 5. 
Hemoglobin equal to or greater than 12 g/dl before each study. 6. Weight greater than 44 kg. 
IRB NUMBER: 2010-435
IRB APPROVAL DATE: 04/27/2015


Exclusion Criteria: 1. Any chronic disease: leukemia, inflammatory bowel disease, cystic 
fibrosis, juvenile rheumatoid arthritis etc, except for diabetes and hypothyroidism. 2. Any 
medications that may affect glucose metabolism. 3. Abnormal AST, ALT, amylase, lipase, 
creatinine (more than 3 times normal values). 4. Lack of a supportive family environment as 
detected by the clinicians and/or social workers. 5. History of substance abuse (evaluated by 
medical history and CRAFFT questionnaire which will be administered at the screening visit). 6. 
Positive pregnancy test in females. 7. Lactating and nursing mothers. The study will include 10 
subjects with T1DM and 10 healthy controls. The study is designed to detect a 20% difference in 
mean area under the curve for glucose for a 270 min period (breakfast). From our previous 
protocols, we have found r > 0.8 between repeated measures and that the standard deviation for 
our excursion measure AUC is approximately 30%. With these specifications, the necessary 
sample size is 8 subjects. With a 20% drop out rate, we would need 10 subjects with T1DM. We 
will also recruit 10 healthy controls for comparison. Study Procedure: Screening: After signing a 
consent form, a screening evaluation will be performed prior to study enrollment. The evaluation 
will consist of a detailed medical history and physical examination (including height, weight, 
vital signs and Tanner staging). Baseline laboratory tests will include: CBC, creatinine, AST, 
ALT, amylase, and lipase. In addition, healthy control subjects will have a diabetes antibody 
panel drawn. A urine pregnancy test will be performed in all female subjects. The approximate 
volume of blood drawn is expected to be 3 ml’s for subjects with T1DM and 11 ml’s for 
controls. Study: The subject must be NPO (except for water) for 8 hours prior to the study. The 
subject will be admitted at 0700. Vital signs, stat hemoglobin (if there is no documented 
hemoglobin in the past 28 days), and pregnancy tests (in females) will be checked. Hemoglobin 
must be >12 g/dl and female subjects must have a negative urine pregnancy test. An intravenous 
line will be placed in the forearm. At around 0800 baseline blood samples will be drawn for: 
glucose, insulin, C-peptide, amylin, GLP-1, and glucagon. In Study A and C, blood for exenatide 
will also be drawn. If blood glucose values are below 70 mg/dl, IV glucose of 5-15 grams will be 
administered to achieve euglycemia (90-130 mg/dl). At around 0830 (0 min), the subjects with 
T1DM will get his/her home dose of long acting insulin (if it has not been administered the night 
before).Insulin Pump users will be on their usual basal rate of rapid acting insulin. For study part 
A, Exenatide will be also be given as a subcutaneous injection of 1.25 mcg. For study part B, 
bolus of rapid acting insulin will also be given based on subjects prescribed regimen. For study 
IRB NUMBER: 2010-435
IRB APPROVAL DATE: 04/27/2015


part C, the subject will receive Exenatide 1.25 micrograms and rapid acting insulin (with a 30-
50% reduction from the usual dose). No medication will be given to subjects in the control arm. 
Following this, the subject will be offered a standard liquid meal of Boost High Protein Drink, 12 
Oz. (360 calories, 50 g of carbohydrates and 12 g of fat) and asked to consume it within a 10-15 
minute period. This will be enriched with 1 gram of [1- 13C] glucose. Blood glucose 
concentrations will be measured at the bedside using an Analox glucose analyzer at -30, -10, 0, 
10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 200, 220, 240, 
270, 300 min. Blood samples will be collected for hormonal analysis of Insulin, C-peptide, 
Amylin at -30, -10, 0, 10, 20, 30, 40, 60, 80, 120, 180, 240, 300 min. Samples for GLP- 1 will be 
collected at -30, 0, 10, 20, 40, 60, 80, 120, 180, 240, 300 min and Glucagon at -30, -10, 0, 10, 20, 
30, 40, 60, 80, 100, 120, 140, 180, 240, 300 min. Blood samples for pK exenatide will only be 
collected in Study A and C at -30, 0, 10, 20, 40, 60, 120, 180, 240, 300 min. A total blood 
volume of 148.7 ml’s will be drawn in study A and study C, and 128.7 ml’s in study B and the 
control study. Expired 13CO2 will be determined in breath samples at 0, 20, 40, 60, 120, 180, 
240, 300 min. During the study, if blood glucose values in a subject are less than 55 mg/dl, IV 
glucose of 5-15 grams will be administered to achieve euglycemia (90-130 mg/dl). 1-2 doses of 
IV glucose should correct hypoglycemia. If more than 3 doses are required to achieve 
euglycemia, the study will be terminated, the subject will be offered a meal tray and blood sugar 
rechecked to ensure euglycemia. If blood sugar at any time is more than 350 with moderate 
ketones, the study will be terminated. At the end of the study at 300 min, lunch will be provided 
(consistent carbohydrate meal) and insulin will be given as per the subject’s prescribed regimen. 
The subject will be discharged home with a designated driver due to the risk of hypoglycemia. 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 
IRB NUMBER: 2010-435
IRB APPROVAL DATE: 04/27/2015


better to bank blood samples and perform hormone analyses as newer assays become available 
rather than repeating the study. 
IRB NUMBER: 2010-435
IRB APPROVAL DATE: 04/27/2015