Amitriptyline in Treating Hypoglycemia

Phase 2

Terminated

Conditions: Hypoglycemia Unawareness
Type1 Diabetes Mellitus

Interventions: Drug: Amitriptyline
Drug: Placebo

Registration Number: NCT03591458

Lead Sponsor: University of Utah

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Amitriptyline	Amitriptyline	Participants will be initiated on 25 mg Amitriptyline daily for two weeks during the Titration Period. Amitriptyline dose will be increased to 50 mg daily for 8 weeks during the Intervention Period. Finally, the dose of Amitriptyline will be reduced to 25 mg daily during the two week Taper Period.
Placebo	Placebo	Participants will be initiated on a daily Placebo capsule matching the 25 mg Amitriptyline during the Titration Period. The daily dose will be changed to the Placebo capsule matching the 50 mg Amitriptyline for 8 weeks during the Intervention Period. Finally, the daily dose will be changed back to the Placebo capsule matching the 25 mg Amitriptyline during the two week Taper period.

Primary Outcome Measures

Name	Time	Method
Glucose Area Under the Curve (AUC): Values < 70 mg/dL	2 Weeks	Continuous Glucose Monitoring (CGM) data will be collected for a 2-week period at the end of the Intervention Phase. The mean AUC for glucose values \< 70 mg/dL will be compared between the Amitriptyline and Placebo arms.
Glucose Area Under the Curve (AUC): Values < 54 mg/dL	2 Weeks	Continuous Glucose Monitoring (CGM) data will be collected for a 2-week period at the end of the Intervention Phase. The mean AUC for glucose values \< 54 mg/dL will be compared between the Amitriptyline and Placebo arms.
Ratio of Self-Reported Hypoglycemic Episodes to Total Hypoglycemic Episodes	2 Weeks	Participants will complete a report of all hypoglycemic events experienced during the 2-week surveillance period at the end of the Intervention Phase. The average ratio of self-reported hypoglycemic episodes to total hypoglycemic episodes recorded by Continuous Glucose Monitoring (CGM) will be compared between the Amitriptyline and Placebo arms.

Secondary Outcome Measures

Name	Time	Method
Average Hypoglycemia Duration With Blood Glucose < 54 mg/dL	2 weeks	Continuous Glucose Monitoring (CGM) data will be collected for a 2-week period at the end of the Intervention Phase. The duration of hypoglycemic episodes for glucose values \< 54 mg/dL will be averaged compared between the Amitriptyline and Placebo arms.
Hypoglycemia Awareness Score by Gold Questionnaire	10 Weeks	Participants will complete the Gold questionnaire for hypoglycemia awareness at the baseline and final Intervention Phase visit. The Gold questionnaire is comprised of one question to evaluate the hypoglycemia awareness, with scores from 1 to 7, representing from normal to minimal/no hypoglycemia awareness. The average change in Gold questionnaire score from baseline to end of treatment will be compared between the Amitriptyline and Placebo arms.
Hypoglycemia Awareness Score by Clarke Questionnaire	10 Weeks	Participants will complete the Clarke questionnaire for hypoglycemia awareness at the baseline and final Intervention Phase visit. The Clarke questionnaire is comprised of eight questions to evaluate the hypoglycemia awareness. The answer for each individual question will represent a score (0 or 1). These scores will be summed together to a final score from 0 to 7, representing from normal to minimal/no hypoglycemia awareness. The average change in Clarke questionnaire score from baseline to end of treatment will be compared between the Amitriptyline and Placebo arms.
Hypoglycemia Awareness Score by Pedersen-Bjergaard Questionnaire	10 Weeks	Participants will complete the Pedersen-Bjergaard questionnaire for hypoglycemia awareness at the baseline and final Intervention Phase visit. The Pederson-Bjergaard questionnaire is comprised of one question to evaluate the hypoglycemia awareness, with answers of "Always", "sometimes", "occasionally", "never" or "Do not know". Each answer will represent an awareness status. The change in Pedersen-Bjergaard questionnaire status from baseline to end of treatment will be compared between the Amitriptyline and Placebo arms.
Total Count of Severe Hypoglycemic Episodes	8 Weeks	Severe hypoglycemic episodes, defined by the need from other to administer treatments for hypoglycemia, as reported by patients will be counted and totaled during the Intervention Phase.
Hypoglycemia Episode Count With Blood Glucose < 70 mg/dL	2 weeks	Continuous Glucose Monitoring (CGM) data will be collected for a 2-week period at the end of the Intervention Phase. The number of hypoglycemic episodes for glucose values \< 70 mg/dL will be compared between the Amitriptyline and Placebo arms.
Hypoglycemia Episode Count With Blood Glucose < 54 mg/dL	2 weeks	Continuous Glucose Monitoring (CGM) data will be collected for a 2-week period at the end of the Intervention Phase. The number of hypoglycemic episodes for glucose values \< 54 mg/dL will be compared between the Amitriptyline and Placebo arms.
Average Hypoglycemia Duration With Blood Glucose < 70 mg/dL	2 weeks	Continuous Glucose Monitoring (CGM) data will be collected for a 2-week period at the end of the Intervention Phase. The duration of hypoglycemic episodes for glucose values \< 70 mg/dL will be averaged compared between the Amitriptyline and Placebo arms.
Hypoglycemia Fear Survey Score	10 Weeks	Participants will complete the Hypoglycemia Fear Survey for hypoglycemia fear assessment at the baseline and final Intervention Phase visit. The Hypoglycemia Fear Survey is comprised of 33 questions to evaluate the hypoglycemia awareness. The answer for each individual question will represent a score (0 to 4). These scores will be summed together to a final score from 0 to 132, representing from normal to minimal/no hypoglycemia awareness. The average change in Hypoglycemia Fear Survey questionnaire score from baseline to end of treatment will be compared between the Amitriptyline and Placebo arms.