Type1 Diabetes Mellitus
Conditions
Brief summary
To demonstrate that a new insulin pump system can prevent low glucose episodes and improve brain function in aged Type 1 diabetes mellitus subjects.
Detailed description
The goals of this proposal are to implement a Close-Loop/Artificial Pancreas (CL/AP) system in older patients with type 1 diabetes mellitus (T1DM) in order to reverse brain metabolic adaptations and restore metabolic sensitivity, hypoglycemia awareness and appropriate hormonal counterregulatory responses (CRR). For purposes of this study we are looking to enroll aged T1DM subjects under insulin pump treatment.
Interventions
DEVICECL/AP system
CL/AP system enabled insulin pump/CGM combination
DEVICEusual diabetic care
usual diabetic care (insulin pump therapy) along with CGM recording
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
The intervention consists of treatment with a CL/AP-enabled insulin pump/CGM combination; subjects in the control group will continue their usual diabetes care (insulin pump therapy) along with CGM recording .
Intervention model description
The design is a single-site, parallel group, randomized clinical trail. Following enrollement and CGM documentation of hypoglycemia during the 4-week run-in period, study participants are randomized to intervention and control groups.
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Provide signed and dated informed consent form * Male or female * Age 50-75 years (at least 50% over the age of 65) * T1DM (\>20 years duration) * C-peptide undetectable * HbA1c of \< 8% * Insulin pump therapy * History of frequent hypoglycemia with unawareness (defined as 2 or more episodes of severe hypoglycemia within one year requiring assistance) and 2 or more glucose values \< 54 mg/dL during the week of Continuous Glucose Monitoring (CGM) (iPRO monitor, Medtronic) prior to enrollment * BMI \<27 kg/m2 * Good general health as evidenced by medical history and blood screening * Willing to comply with all study procedures and be available for the duration of the study * Willing to fast for a limited time period on the morning of a clamp study
Exclusion criteria
* Significant diabetic complications (untreated proliferative retinopathy, creatinine ≥1.5 mg/dl, urinary albumin levels 300 mg/day, autonomic neuropathy, painful peripheral neuropathy) * Significant alcohol intake and vegetarian diet since both are known to have an impact on counterregulation and brain metabolism * Any contraindications for MRI scanning, including presence of metallic implants or claustrophobia. * Heavy exercise on a regular basis (i.e. marathon runners) * Known allergic reactions to components of the study product(s) * Treatment with another investigational drug or other intervention * Active infection including hepatitis C, hepatitis B, HIV * Any past or current history of alcohol or substance abuse * Psychiatric or neurological disorders under active treatment * Baseline hemoglobin \< 10.5 g/dL in females, or \< 12.5 g/dL in males. Blood donation within 30 days of the study * History of coagulopathy or medical condition requiring long-term anticoagulant therapy (low-dose aspirin treatment is allowed) * Co-existing cardiac, liver, and kidney disease * Abnormal liver function tests * Women that are on oral contraceptives, post-menopausal, pregnant (as assessed by pregnancy test that will be performed on female participants at reproductive age), or lactating. * Any medical condition or medication that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Alternate Fuel Uptake | Baseline to 8 - 10 weeks | Change in brain alternate fuel uptake under hypoglycemia was measured by assessing the percent enrichment of Glutamine 4 (Gln4). Change was measured by subtracting follow up from baseline. Astrocytic glutamine C4 enrichment is a measure of brain acetate metabolism (an alternate fuel to glucose). Previous studies have shown that in people who have been exposed to frequent hypoglycemic episodes, glutamine C4 enrichment increases. Therefore, we expected a reduction in Glutamine C4 percent enrichment in the follow up NMR scans in the intervention group who avoided frequent hypoglycemic episodes through the CL/AP system. In addition, there is no specific cut off value used for Glutamine C4 enrichment, rather a change or reduction was expected and noted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognitive Function: MOCA | Baseline to 8-10 weeks | The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 30 points; a score of 26 or above is considered normal. Change was calculated by subtracting follow up from baseline. https://www.parkinsons.va.gov/resources/MoCA-Instructions-English.pdf |
| Change in Cognitive Function: Trail Test A | Baseline to 8-10 weeks | Trail making test (TMT) A is a test of visual attention and task switching. It provides information about visual search speed, speed of processing and executive function. Time is measured in seconds. The typical average time to complete the test is 29 seconds, a deficient performance would be \>78 seconds; most people are able to complete in 90 seconds. Change was calculated by subtracting follow up from baseline. |
| Change in Cognitive Function: Trail Test B | Baseline to 8-10 weeks | Trail making test (TMT) B is a test of visual attention and task switching. It provides information about visual search speed, speed of processing and executive function. Time will be measured in seconds. The typical average time to complete the test is 75 seconds, a deficient performance would be \>273 seconds; most people are able to complete in 180 seconds. Change was calculated by subtracting follow up from baseline. |
| Change in Cognitive Function: Grooved Pegboard Test | Baseline to 8-10 weeks | The grooved pegboard test is a manipulative dexterity test that assessed psychomotor speed, fine motor control, and rapid-visual motor coordination. It consists of a small board of holes with randomly positioned slots. Pegs with a key along one side must be rotated to match the hole before they can be inserted. The task was completed using the dominant hand. Time was measured in seconds. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CL/AP System To improved glycemic control and strict avoidance of hypoglycemia via 8-week use of a CL/AP system (closed-loop/artificial pancreas) reverses brain metabolic adaptations in older adult T1DM patients.
CL/AP system: CL/AP system enabled insulin pump/CGM combination | 4 |
| Usual Care Subjects in this control group will continue their usual diabetic care (insulin pump therapy) along with CGM recording.
usual diabetic care: usual diabetic care (insulin pump therapy) along with CGM recording | 3 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Participant Unable to Manage Device | 1 | 0 |
Baseline characteristics
| Characteristic | CL/AP System | Usual Care | Total |
|---|---|---|---|
| Age, Customized Age Categorized 50-59 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Customized Age Categorized 60-69 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Customized Age Categorized 70-79 years | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 7 Participants |
| Region of Enrollment United States | 4 participants | 3 participants | 7 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 |
| other Total, other adverse events | 0 / 4 | 0 / 3 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 |
Outcome results
Primary
Brain Alternate Fuel Uptake
Change in brain alternate fuel uptake under hypoglycemia was measured by assessing the percent enrichment of Glutamine 4 (Gln4). Change was measured by subtracting follow up from baseline. Astrocytic glutamine C4 enrichment is a measure of brain acetate metabolism (an alternate fuel to glucose). Previous studies have shown that in people who have been exposed to frequent hypoglycemic episodes, glutamine C4 enrichment increases. Therefore, we expected a reduction in Glutamine C4 percent enrichment in the follow up NMR scans in the intervention group who avoided frequent hypoglycemic episodes through the CL/AP system. In addition, there is no specific cut off value used for Glutamine C4 enrichment, rather a change or reduction was expected and noted.
Time frame: Baseline to 8 - 10 weeks
Population: Only 2 participants (per protocol complete cases) in the intervention had data that was analyzable due to technical issues that occured with the usual care group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CL/AP System | Brain Alternate Fuel Uptake | Baseline | 10.855 percent enrichment of Gln4 | Standard Deviation 10.642 |
| CL/AP System | Brain Alternate Fuel Uptake | Follow Up | 7.28 percent enrichment of Gln4 | Standard Deviation 8.888 |
| CL/AP System | Brain Alternate Fuel Uptake | Change | 3.57 percent enrichment of Gln4 | Standard Deviation 1.754 |
Secondary
Change in Cognitive Function: Grooved Pegboard Test
The grooved pegboard test is a manipulative dexterity test that assessed psychomotor speed, fine motor control, and rapid-visual motor coordination. It consists of a small board of holes with randomly positioned slots. Pegs with a key along one side must be rotated to match the hole before they can be inserted. The task was completed using the dominant hand. Time was measured in seconds.
Time frame: Baseline to 8-10 weeks
Population: Only those that completed both assessments (did not drop out) were included in the analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CL/AP System | Change in Cognitive Function: Grooved Pegboard Test | Baseline | 105 seconds | Standard Deviation 64 |
| CL/AP System | Change in Cognitive Function: Grooved Pegboard Test | Follow Up | 100 seconds | Standard Deviation 53 |
| CL/AP System | Change in Cognitive Function: Grooved Pegboard Test | Change | 5 seconds | Standard Deviation 11 |
| Usual Care | Change in Cognitive Function: Grooved Pegboard Test | Baseline | 78 seconds | Standard Deviation 13 |
| Usual Care | Change in Cognitive Function: Grooved Pegboard Test | Follow Up | 73 seconds | Standard Deviation 18 |
| Usual Care | Change in Cognitive Function: Grooved Pegboard Test | Change | 5 seconds | Standard Deviation 8 |
Secondary
Change in Cognitive Function: MOCA
The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 30 points; a score of 26 or above is considered normal. Change was calculated by subtracting follow up from baseline. https://www.parkinsons.va.gov/resources/MoCA-Instructions-English.pdf
Time frame: Baseline to 8-10 weeks
Population: Only those that completed both assessments (did not drop out) were included in the analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CL/AP System | Change in Cognitive Function: MOCA | Baseline | 23 units on a scale | Standard Deviation 0 |
| CL/AP System | Change in Cognitive Function: MOCA | Follow Up | 25.5 units on a scale | Standard Deviation 0.707 |
| CL/AP System | Change in Cognitive Function: MOCA | Change | -2.5 units on a scale | Standard Deviation 0.707 |
| Usual Care | Change in Cognitive Function: MOCA | Baseline | 27 units on a scale | Standard Deviation 2 |
| Usual Care | Change in Cognitive Function: MOCA | Follow Up | 29 units on a scale | Standard Deviation 0 |
| Usual Care | Change in Cognitive Function: MOCA | Change | -2 units on a scale | Standard Deviation 2 |
Secondary
Change in Cognitive Function: Trail Test A
Trail making test (TMT) A is a test of visual attention and task switching. It provides information about visual search speed, speed of processing and executive function. Time is measured in seconds. The typical average time to complete the test is 29 seconds, a deficient performance would be \>78 seconds; most people are able to complete in 90 seconds. Change was calculated by subtracting follow up from baseline.
Time frame: Baseline to 8-10 weeks
Population: Only those that completed both assessments (did not drop out) were included in the analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CL/AP System | Change in Cognitive Function: Trail Test A | Baseline | 63 seconds | Standard Deviation 39 |
| CL/AP System | Change in Cognitive Function: Trail Test A | Follow Up | 34 seconds | Standard Deviation 3 |
| CL/AP System | Change in Cognitive Function: Trail Test A | Change | 29 seconds | Standard Deviation 42 |
| Usual Care | Change in Cognitive Function: Trail Test A | Baseline | 28 seconds | Standard Deviation 11 |
| Usual Care | Change in Cognitive Function: Trail Test A | Follow Up | 21 seconds | Standard Deviation 5 |
| Usual Care | Change in Cognitive Function: Trail Test A | Change | 7 seconds | Standard Deviation 16 |
Secondary
Change in Cognitive Function: Trail Test B
Trail making test (TMT) B is a test of visual attention and task switching. It provides information about visual search speed, speed of processing and executive function. Time will be measured in seconds. The typical average time to complete the test is 75 seconds, a deficient performance would be \>273 seconds; most people are able to complete in 180 seconds. Change was calculated by subtracting follow up from baseline.
Time frame: Baseline to 8-10 weeks
Population: Only those that completed both assessments (did not drop out) were included in the analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CL/AP System | Change in Cognitive Function: Trail Test B | Baseline | 86 seconds | Standard Deviation 22 |
| CL/AP System | Change in Cognitive Function: Trail Test B | Follow Up | 68 seconds | Standard Deviation 23 |
| CL/AP System | Change in Cognitive Function: Trail Test B | Change | 18 seconds | Standard Deviation 1 |
| Usual Care | Change in Cognitive Function: Trail Test B | Baseline | 54 seconds | Standard Deviation 13 |
| Usual Care | Change in Cognitive Function: Trail Test B | Follow Up | 42 seconds | Standard Deviation 7 |
| Usual Care | Change in Cognitive Function: Trail Test B | Change | 12 seconds | Standard Deviation 17 |