Type1 Diabetes MellitusPhase 2NCT03591458
Amitriptyline in Treating Hypoglycemia
A Phase 2 study testing Amitriptyline in people with Type1 Diabetes Mellitus and Hypoglycemia Unawareness, run by University of Utah at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 60 years
- Conditions the study is for
- Type1 Diabetes Mellitus, Hypoglycemia Unawareness
- What is being tested?
- Amitriptyline
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 2 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Aug 2018to 3 Jun 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition
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.
Read the 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.
- Conditions
- Type1 Diabetes Mellitus, Hypoglycemia Unawareness
- Being tested
- Amitriptyline, Placebo
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AmitriptylineDrug
Participants will receive a supply of Amitriptyline capsules for titration, intervention, and taper periods.
PlaceboDrug
Participants will receive a supply of Placebo capsules, matching those of Amitriptyline, for the titration, intervention, and taper periods
| Study group | Role | What they receive |
|---|---|---|
| Amitriptyline | Experimental | 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. Receives: Drug: Amitriptyline |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 2 Weeks
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.
Measured: 2 Weeks
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.
Measured: 2 Weeks
Secondary outcomes (9)
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.
Measured: 8 Weeks
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.
Measured: 2 weeks
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.
Measured: 2 weeks
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.
Measured: 2 weeks
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.
Measured: 2 weeks
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.
Measured: 10 Weeks
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.
Measured: 10 Weeks
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.
Measured: 10 Weeks
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.
Measured: 10 Weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jul 2018
- Study start1 Aug 2018
- Primary completion3 Jun 2019
- Study completion3 Jun 2019
Why it stopped: Slow subject enrollment, unable to complete trial in a timely manner
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Type1 Diabetes MellitusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Double-blind, randomized, placebo control
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Utah
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Yu Kuei Lin, M.D., Principal investigator, University of Utah
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03591458
- Sponsor's protocol ID
- IRB_00110853
- Status last verified
- Jul 2019
- First submitted
- 8 Jul 2018
- Last updated
- 22 Jul 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition
- ClinicalTrials.gov ID
- NCT03591458
- Acronym / sponsor ID
- IRB_00110853
- Conditions
- Type1 Diabetes Mellitus, Hypoglycemia Unawareness
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Slow subject enrollment, unable to complete trial in a timely manner
- Enrolment
- 2 participants (actual)
- Lead sponsor
- University of UtahUniversity, hospital or other
- Study start
- 1 Aug 2018 (actual)
- Primary completion
- 3 Jun 2019 (actual)
- Study completion
- 3 Jun 2019 (actual)
- First posted
- 19 Jul 2018 (actual)
- Results
- Posted 22 Jul 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Double-blind, randomized, placebo control
| Arm | Type | Receives |
|---|---|---|
| Amitriptyline | Experimental | Drug: AmitriptylineParticipants 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 comparator | Drug: PlaceboParticipants 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. |
Who may qualify
- Ages
- 21 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AmitriptylineParticipants will receive a supply of Amitriptyline capsules for titration, intervention, and taper periods. | Drug | Amitriptyline |
| PlaceboParticipants will receive a supply of Placebo capsules, matching those of Amitriptyline, for the titration, intervention, and taper periods | Drug | Placebo |
Primary outcome
Glucose Area Under the Curve (AUC): Values < 70 mg/dL
Time frame: 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
Time frame: 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
Time frame: 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.
9 secondary outcomes
Total Count of Severe Hypoglycemic Episodes
Time frame: 8 Weeks
Hypoglycemia Episode Count With Blood Glucose < 70 mg/dL
Time frame: 2 weeks
Hypoglycemia Episode Count With Blood Glucose < 54 mg/dL
Time frame: 2 weeks
Average Hypoglycemia Duration With Blood Glucose < 70 mg/dL
Time frame: 2 weeks
Average Hypoglycemia Duration With Blood Glucose < 54 mg/dL
Time frame: 2 weeks
Hypoglycemia Awareness Score by Gold Questionnaire
Time frame: 10 Weeks
Hypoglycemia Awareness Score by Clarke Questionnaire
Time frame: 10 Weeks
Hypoglycemia Awareness Score by Pedersen-Bjergaard Questionnaire
Time frame: 10 Weeks
Hypoglycemia Fear Survey Score
Time frame: 10 Weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jul 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yu Kuei Lin, M.D. principal investigator
University of Utah
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Amitriptyline in people with Type1 Diabetes Mellitus and Hypoglycemia Unawareness, run by University of Utah at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 22 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Jul 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Glucose Area Under the Curve (AUC): Values < 70 mg/dL (time frame: 2 Weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jul 2019; AzTrials last refreshed its copy on 27 Oct 2026.