Clinical trial NCT03591458: Amitriptyline in Treating Hypoglycemia
Official title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Type1 Diabetes Mellitus
Hypoglycemia Unawareness
Lead sponsor: University of Utah
Sponsor class: OTHER
First posted: 2018-07-19
Enrollment: 2
Sex: ALL
Minimum age (years): 21
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind, randomized, placebo control
Primary purpose: TREATMENT

Brief summary: Patients with type 1 diabetes mellitus (T1DM) commonly experience hypoglycemia and develop impaired awareness of hypoglycemia. Many patients using continuous glucose monitoring (CGM) system to mitigate these complications, but continue to spend a significant amount of time in hypoglycemia. The long-term goal is to develop novel and readily available therapeutic approaches to improve hypoglycemia course and awareness in T1DM patients. The objective of this study is to determine whether amitriptyline will improve hypoglycemia course and the ability to recognize hypoglycemic events in T1DM patients who are using CGM.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Glucose Area Under the Curve (AUC): Values < 70 mg/dL
timeFrame: 2 Weeks
measure: Glucose Area Under the Curve (AUC): Values < 54 mg/dL
timeFrame: 2 Weeks
measure: Ratio of Self-Reported Hypoglycemic Episodes to Total Hypoglycemic Episodes
timeFrame: 2 Weeks
Secondary outcomes:
measure: Total Count of Severe Hypoglycemic Episodes
timeFrame: 8 Weeks
measure: Hypoglycemia Episode Count With Blood Glucose < 70 mg/dL
timeFrame: 2 weeks
measure: Hypoglycemia Episode Count With Blood Glucose < 54 mg/dL
timeFrame: 2 weeks
measure: Average Hypoglycemia Duration With Blood Glucose < 70 mg/dL
timeFrame: 2 weeks
measure: Average Hypoglycemia Duration With Blood Glucose < 54 mg/dL
timeFrame: 2 weeks
measure: Hypoglycemia Awareness Score by Gold Questionnaire
timeFrame: 10 Weeks
measure: Hypoglycemia Awareness Score by Clarke Questionnaire
timeFrame: 10 Weeks
measure: Hypoglycemia Awareness Score by Pedersen-Bjergaard Questionnaire
timeFrame: 10 Weeks
measure: Hypoglycemia Fear Survey Score
timeFrame: 10 Weeks
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Utah
name: Yu Kuei Lin, M.D.
role: PRINCIPAL_INVESTIGATOR
References: