search
Back to results

Amitriptyline in Treating Hypoglycemia

Primary Purpose

Type1 Diabetes Mellitus, Hypoglycemia Unawareness

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Amitriptyline
Placebo
Sponsored by
University of Utah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type1 Diabetes Mellitus

Eligibility Criteria

21 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Utah

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Amitriptyline

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Glucose Area Under the Curve (AUC): Values < 70 mg/dL
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
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
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

Total Count of Severe Hypoglycemic Episodes
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
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
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
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.
Average Hypoglycemia Duration With Blood Glucose < 54 mg/dL
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
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
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
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.
Hypoglycemia Fear Survey Score
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.

Full Information

First Posted
July 8, 2018
Last Updated
July 12, 2019
Sponsor
University of Utah
search

1. Study Identification

Unique Protocol Identification Number
NCT03591458
Brief Title
Amitriptyline in Treating Hypoglycemia
Official Title
The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Terminated
Why Stopped
Slow subject enrollment, unable to complete trial in a timely manner
Study Start Date
August 1, 2018 (Actual)
Primary Completion Date
June 3, 2019 (Actual)
Study Completion Date
June 3, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Utah

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type1 Diabetes Mellitus, Hypoglycemia Unawareness

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Double-blind, randomized, placebo control
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Amitriptyline
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Amitriptyline
Intervention Description
Participants will receive a supply of Amitriptyline capsules for titration, intervention, and taper periods.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Participants will receive a supply of Placebo capsules, matching those of Amitriptyline, for the titration, intervention, and taper periods
Primary Outcome Measure Information:
Title
Glucose Area Under the Curve (AUC): Values < 70 mg/dL
Description
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.
Time Frame
2 Weeks
Title
Glucose Area Under the Curve (AUC): Values < 54 mg/dL
Description
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.
Time Frame
2 Weeks
Title
Ratio of Self-Reported Hypoglycemic Episodes to Total Hypoglycemic Episodes
Description
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.
Time Frame
2 Weeks
Secondary Outcome Measure Information:
Title
Total Count of Severe Hypoglycemic Episodes
Description
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.
Time Frame
8 Weeks
Title
Hypoglycemia Episode Count With Blood Glucose < 70 mg/dL
Description
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.
Time Frame
2 weeks
Title
Hypoglycemia Episode Count With Blood Glucose < 54 mg/dL
Description
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.
Time Frame
2 weeks
Title
Average Hypoglycemia Duration With Blood Glucose < 70 mg/dL
Description
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.
Time Frame
2 weeks
Title
Average Hypoglycemia Duration With Blood Glucose < 54 mg/dL
Description
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.
Time Frame
2 weeks
Title
Hypoglycemia Awareness Score by Gold Questionnaire
Description
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.
Time Frame
10 Weeks
Title
Hypoglycemia Awareness Score by Clarke Questionnaire
Description
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.
Time Frame
10 Weeks
Title
Hypoglycemia Awareness Score by Pedersen-Bjergaard Questionnaire
Description
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.
Time Frame
10 Weeks
Title
Hypoglycemia Fear Survey Score
Description
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.
Time Frame
10 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yu Kuei Lin, M.D.
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Amitriptyline in Treating Hypoglycemia

We'll reach out to this number within 24 hrs