Amitriptyline in Treating Hypoglycemia

Poorly controlled T1DM can lead to serious and devastating complications, including
microvascular (retinopathy, neuropathy and nephropathy) and cardiovascular disease. Both
diabetic microvascular and cardiovascular complications can be reduced by intensive insulin
therapy and strict blood glucose aiming for hemoglobin A1C (HbA1c) less or equal to 7%.
However, a tighter glycemic control correlates with a higher incidence of hypoglycemia and
severe hypoglycemia. As well, recurrent episodes of hypoglycemia reduce patients' ability to
recognize hypoglycemic episodes (a condition termed impaired awareness of hypoglycemia).
Impaired awareness of hypoglycemia is also associated with an increased risk of severe
hypoglycemia. Severe hypoglycemia can lead to seizures, emergency room
visits/hospitalization, fear of hypoglycemia, compromised quality of life and potentially
death. Thus, hypoglycemia and impaired awareness of hypoglycemia are major barriers to
optimal glycemic control.

Real-time continuous glucose monitoring (rtCGM) is a technique which measures interstitial
glucose levels every five minutes to estimate coincidental blood glucose levels. A rtCGM will
alert patients of hyper/hypoglycemic events at seg glucose thresholds and when the blood
glucose levels are rapidly rising/declining. However, many patients using rtCGM continue to
have impaired awareness of hypoglycemia and spend a significant amount of time in
hypoglycemia.

In an animal model, amitriptyline, a tricyclic antidepressant, demonstrated its ability to
completely restore hypoglycemia awareness. This potential effect of amitriptyline on human,
however, has not been tested.

In the current study, amitriptyline will be studied as an adjuvant treatment of rtCGM to
further improve hypoglycemia course and T1DM patients' ability to recognize hypoglycemic
episode.

Inclusion Criteria:

- Subjects with Type 1 Diabetes Mellitus for at least 5 years or more

- Age between 21 to 60 years old

- HbA1c less or equal to 9% with the latest measurement within the last 3 months

- Use of real time Continuous Glucose Monitoring (rtCGM) providing continuous glucose
data points for at least 3 months, and at least 80% of CGM readings available over the
last 2-week period

- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines

Exclusion Criteria:

- Ongoing or recent history of major depressive disorder, or other ongoing major
psychiatric disorders

- History of anti-depressant use within the last three months

- Insulin pump linked to a CGM with programmed automatic insulin adjustment or
suspension

- History of advanced cardiac, liver, kidney or neurological disease

- Active malignancy

- Uncontrolled Human Immunodeficiency Virus diseases

- Advanced diabetic retinopathy, neuropathy, or nephropathy

- Frequent acetaminophen use which can disrupt CGM accuracy

- Pregnancy or female of child-bearing potential unable to practice effective
contraception during the study period

- Breastfeeding female, or female with prospective plan to initiate breastfeeding

- Ongoing history of alcohol abuse

- Contraindication to amitriptyline use, including hypersensitivity to amitriptyline or
any component of the formulation, co-administration with or within 14 days of
Monoamine Oxidase Inhibitors and co-administration with cisapride

- Inability to understand or cooperate with study procedures, including taking study
drugs and recording hypoglycemic symptoms.

The participants meeting the above criteria will enter "Run-in Period". At the Visit 2, the
following additional exclusion criteria will be applied before study drug randomization:

- < 80% of CGM readings available over the last 2-week period

- Time spent in hypoglycemia (i.e., < 70 mg/dL) for < 5% over a 2-week period on based
on CGM reading.