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Slow subject enrollment, unable to complete trial in a timely manner
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Amitriptyline | Drug | Participants will receive a supply of Amitriptyline capsules for titration, intervention, and taper periods. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 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. | 2 Weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 8 Weeks |
| Hypoglycemia Episode Count With Blood Glucose < 70 mg/dL |
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Inclusion Criteria:
Exclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Yu Kuei Lin, M.D. | University of Utah | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Utah | Salt Lake City | Utah | 84132 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Amitriptyline | Participants initiated on 25 mg Amitriptyline daily for two weeks during the Titration Period. Amitriptyline dose was increased to 50 mg daily for 8 weeks during the Intervention Period. Finally, the dose of Amitriptyline was reduced to 25 mg daily during the two week Taper Period. |
| FG001 | Placebo | Participants initiated on a daily Placebo capsule matching the 25 mg Amitriptyline during the Titration Period. The daily dose was changed to the Placebo capsule matching the 50 mg Amitriptyline for 8 weeks during the Intervention Period. Finally, the daily dose was changed back to the Placebo matching the 25 mg Amitriptyline during the two week Taper Period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Amitriptyline | Participants initiated on 25 mg Amitriptyline daily for two weeks during the Titration Period. Amitriptyline dose was increased to 50 mg daily for 8 weeks during the Intervention Period. Finally, the dose of Amitriptyline was reduced to 25 mg daily during the two week Taper Period. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment. | Posted | 2 Weeks |
|
10 Weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Amitriptyline | Participants initiated on 25 mg Amitriptyline daily for two weeks during the Titration Period. Amitriptyline dose was increased to 50 mg daily for 8 weeks during the Intervention Period. Finally, the dose of Amitriptyline was reduced to 25 mg daily during the two week Taper Period. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dry Mouth | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Scott Low | University of Utah | 801-585-1380 | scott.low@hsc.utah.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 24, 2019 | Jun 5, 2019 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 24, 2019 | Jun 5, 2019 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000639 | Amitriptyline |
| ID | Term |
|---|---|
| D003986 | Dibenzocycloheptenes |
| D001567 | Benzocycloheptenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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Double-blind, randomized, placebo control
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| Placebo | Drug | Participants will receive a supply of Placebo capsules, matching those of Amitriptyline, for the titration, intervention, and taper periods |
|
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. |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 10 Weeks |
| Placebo |
Participants initiated on a daily Placebo capsule matching the 25 mg Amitriptyline during the Titration Period. The daily dose was changed to the Placebo capsule matching the 50 mg Amitriptyline for 8 weeks during the Intervention Period. Finally, the daily dose was changed back to the Placebo matching the 25 mg Amitriptyline during the two week Taper Period. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 |
| 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. Placebo: Participants will receive a supply of Placebo capsules, matching those of Amitriptyline, for the titration, intervention, and taper periods |
|
| Primary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 2 Weeks |
|
|
| Primary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 2 Weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 8 Weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 2 weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 2 weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 2 weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 2 weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 10 Weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 10 Weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 10 Weeks |
|
|
| Secondary | 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. | No analysis conducted due to small sample size; study terminated due to low enrollment | Posted | 10 Weeks |
|
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| 0 |
| 1 |
| 0 |
| 1 |
| 1 |
| 1 |
| EG001 | Placebo | Participants initiated on a daily Placebo capsule matching the 25 mg Amitriptyline during the Titration Period. The daily dose was changed to the Placebo capsule matching the 50 mg Amitriptyline for 8 weeks during the Intervention Period. Finally, the daily dose was changed back to the Placebo matching the 25 mg Amitriptyline during the two week Taper Period. | 0 | 1 | 0 | 1 | 0 | 1 |
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| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |