Diabetes Mellitus, Type 1
Conditions
Brief summary
The purpose of this study is to test if a specific research medication could increase the response to low blood glucose in people with type 1 diabetes. The response of the body to low blood sugar will be measured in healthy people as a reference point.
Detailed description
This is a placebo-controlled, double-blinded, within-subject, cross-over phase 2a study. In randomized order, (Latin square, randomly assigned to placebo-active and active-placebo periods) and in a double-blinded manner, the participants with T1D received 14 days of daily dosing with MBX-2982 (or placebo), taken at the same time each day after breakfast. The last dose of treatment/placebo was given when the glucose tracer infusion for the euglycemic/hypoglycemic-glucose clamp started. Participants with T1D underwent two euglycemic-hypoglycemic clamps (induction of controlled hypoglycemia by an insulin infusion), using a within-subject cross-over design, with the two clamps separated by approximately four weeks, that is, two weeks of drug washout followed by two weeks of treatment with the alternative therapy. Glucagon, hepatic glucose production and other counter-regulatory hormonal responses were assessed during hypoglycemia. After completion of the first clamp study, participants did not receive any study medication for two weeks (washout phase) and then begin 14 days of the other arm (placebo or MBX-2982) in a double-blinded manner, followed by a repeat euglycemic-hypoglycemic clamp study. During treatment on each arm and during wash out phase, a blinded CGM was used to assess daily and nocturnal patterns of glycemia. On the day preceding a clamp study, while admitted to the research unit, a standardized meal test was used to assess fasting and postprandial glucagon, GLP-1 and GIP secretion. A healthy normal volunteer cohort with no diabetes was enrolled in the study for 14 days for comparison of normal responses to insulin induced hypoglycemia.
Interventions
DRUGPlacebo
Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)
DRUGStudy Medication (MBX-2982)
Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)
OTHERNo medication for this group
This group will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes.
Sponsors
AdventHealth Translational Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Type 1 diabetes cohort: 1. Age 20-60 years 2. Diagnosis of T1DM according to American Diabetes Association (ADA) criteria continuously requiring insulin for survival 3. Diabetes diagnosis performed more than 5 years before enrollment 4. Fasting C-peptide levels \< 0.7 ng/mL with a concurrent plasma glucose concentration \> 90 mg/dL (Labs may need to be repeated if the Plasma glucose is \< 90 mg/dL) 5. For female participants: must be \> 6 months post-partum and not lactating and agrees not to become pregnant during the study and for at least 2 weeks after the last dose of the study medication. For male participants: agrees not to donate sperm or not to get a woman pregnant during the study and for at least 2 weeks after the last dose of the study medication. Healthy subject cohort: 1. Age 20-60 years 2. General good health 3. Creatinine clearance \>80 mL/min based on CKD-EPI equation 4. Fasting blood glucose (FBG) \>70 mg/dL and \<100 mg/dL 5. No history of diabetes 6. For female participants: must be \> 6 months post-partum and not lactating and agrees not to become pregnant during the study
Exclusion criteria
1. BMI \>35 kg/m2 and \<18.5 kg/m2 for females and BMI \>35 kg/m2 and \<20 kg/m2 for males. 2. Increase or decrease body weight greater than 3kg in the 3 months before enrollment. 3. Evidence by history, ECG or exams of clinically significant cardiovascular disease (unstable angina, myocardial infarction or coronary revascularization within 6 months, clinically significant abnormalities on ECG, presence of cardiac pacemaker, implanted cardiac defibrillator) 4. Evidence of autonomic neuropathy 5. Liver disease (AST or ALT \>2.5 times the upper limit of normal) 6. Kidney disease (creatinine \>1.6 mg/dl or estimated GFR \<60 ml/min). 7. Dyslipidemia, including triglycerides \>500 mg/dl, LDL \>200 mg/dl or unstable hyperlipidemia. Treatment with a single lipid lowering agents is allowed if stable within the previous 3 months. 8. Anemia (hemoglobin \<12 g/dl in men, \<11 g/dl in women) 9. Thyroid dysfunction (suppressed TSH, elevated TSH \<10 µIU/ml if symptomatic or elevated TSH \>10 µIU/ml if asymptomatic) 10. Uncontrolled hypertension (BP \>160 mmHg systolic or \>100 mmHg diastolic) or treatment with more than 2 antihypertensive medications. 11. Current use of beta-adrenergic blocking agents or their use was stopped less than one month before recruitment 12. History of cancer within the last 5 years (skin cancers, with the exception of melanoma, may be acceptable) 13. History of organ transplant 14. History of HIV, active Hepatitis B or C, or Tuberculosis 15. Pregnancy, lactation or 6 months postpartum from the scheduled date of screening lab collection 16. Females of childbearing potential (any female except those with tubal ligation, hysterectomy, or absence of menses \>2 years) unwilling to use an approved method of contraception (one medically accepted method of contraception with ≥99% effectiveness when used consistently and correctly). Male participants: he or he and his partner unwilling to use an approved method of contraception with ≥99% effectiveness when used consistently and correctly 17. History of Major Depression in the last 5 years 18. History of an eating disorder 19. History of bariatric surgery 20. History of drug or alcohol abuse (\> 3 drinks per day) within the last 5 years 21. Self-report of marijuana use ≥3 days/week in any form 22. Psychiatric disease prohibiting adherence to study protocol 23. Current use of oral or injectable anti-hyperglycemic agents: metformin, sulfonylureas, DPP IV inhibitors, SGLT-2 inhibitors, thiazolidinediones, acarbose, GLP-1 analogs 24. Initiation or change in hormone replacement therapy within the past 3 months (including, but not limited to thyroid hormone or estrogen replacement therapy). Hormone based contraception is acceptable. 25. Use of any medications known to influence glucose, fat and/or energy metabolism (e.g., growth hormone therapy, glucocorticoids \[steroids\], prescribed medications for weight loss, etc.). Patients on medications with acute effects on glucose metabolism used for other indications (certain antidepressants, ADHD and antiepileptic medications) may be enrolled if they have been on chronic, stable doses (≥6 months) 26. Uncontrolled seizure disorder 27. Current night shift worker 28. Presence of any condition that, in the opinion of the Investigator, compromises participant safety or data integrity or the participant's ability to complete study visits 29. Unwilling and/or unable to follow and comply with scheduled visits and protocol requirements Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Glucagon Concentration During Hypoglycemia | Day 14, Day 42 | Maximal glucagon concentration during insulin induced hypoglycemia. This was measured during the hypoglycemic steady state of the hyper-insulinemic euglycemic-hypoglycemic clamp study. |
| Total Area Under the Curve (AUC) for Glucagon During Hypoglycemia. | Day 14, Day 42 | This outcome was measured during the hypoglycemic steady state of the hyper-insulinemic euglycemic hypoglycemic clamp study. Total area under the curve (AUC) for glucagon was measured during the time points of 120 minutes to 140 minutes of the clamp. |
| Incremental AUC for Glucagon During Hypoglycemia (Above Baseline Levels During Euglycemia) | Day 14, Day 42 | This is the difference between the AUC during the hypoglycemic steady state (time points 120 - 140 mins of clamp) and the baseline glucagon levels during euglycemic steady state (timepoints 60 min - 80 mins of the clamp) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Type 1 Diabetes on MBX-2982 or Placebo Each group will be randomized to receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)
This will be followed by a second study period in which they will be crossed over to the other treatment. | 18 |
| Healthy Volunteers This group will not receive any medication. It will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes. | 9 |
| Total | 27 |
Baseline characteristics
| Characteristic | Type 1 Diabetes on MBX-2982 or Placebo | Healthy Volunteers | Total |
|---|---|---|---|
| Age, Continuous | 38.3 years STANDARD_DEVIATION 12 | 38.2 years STANDARD_DEVIATION 8.5 | 38.3 years STANDARD_DEVIATION 10.8 |
| Body mass index | 25.6 kg/m2 STANDARD_DEVIATION 3.9 | 25.4 kg/m2 STANDARD_DEVIATION 2.5 | 25.5 kg/m2 STANDARD_DEVIATION 3.4 |
| Race/Ethnicity, Customized Black | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 13 Participants | 5 Participants | 18 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 7 Participants | 23 Participants |
| Region of Enrollment United States | 18 Participants | 9 Participants | 27 Participants |
| Sex: Female, Male Female | 9 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 15 Participants |
| Weight | 74.4 Kilograms STANDARD_DEVIATION 13.4 | 73.1 Kilograms STANDARD_DEVIATION 12.1 | 74.0 Kilograms STANDARD_DEVIATION 12.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 | 0 / 9 |
| other Total, other adverse events | 4 / 18 | 5 / 18 | 0 / 9 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 9 |
Outcome results
Primary
Incremental AUC for Glucagon During Hypoglycemia (Above Baseline Levels During Euglycemia)
This is the difference between the AUC during the hypoglycemic steady state (time points 120 - 140 mins of clamp) and the baseline glucagon levels during euglycemic steady state (timepoints 60 min - 80 mins of the clamp)
Time frame: Day 14, Day 42
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1D on MBX-2982 | Incremental AUC for Glucagon During Hypoglycemia (Above Baseline Levels During Euglycemia) | 327.9 pg*min/mL | Standard Deviation 257.9 |
| T1D on Placebo | Incremental AUC for Glucagon During Hypoglycemia (Above Baseline Levels During Euglycemia) | 467.8 pg*min/mL | Standard Deviation 435.7 |
| Healthy Normal Volunteers | Incremental AUC for Glucagon During Hypoglycemia (Above Baseline Levels During Euglycemia) | 2445.4 pg*min/mL | Standard Deviation 1346.4 |
Primary
Maximal Glucagon Concentration During Hypoglycemia
Maximal glucagon concentration during insulin induced hypoglycemia. This was measured during the hypoglycemic steady state of the hyper-insulinemic euglycemic-hypoglycemic clamp study.
Time frame: Day 14, Day 42
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1D on MBX-2982 | Maximal Glucagon Concentration During Hypoglycemia | 19.9 pg/mL | Standard Deviation 12.6 |
| T1D on Placebo | Maximal Glucagon Concentration During Hypoglycemia | 22.5 pg/mL | Standard Deviation 16.8 |
| Healthy Normal Volunteers | Maximal Glucagon Concentration During Hypoglycemia | 82.7 pg/mL | Standard Deviation 39.7 |
Primary
Total Area Under the Curve (AUC) for Glucagon During Hypoglycemia.
This outcome was measured during the hypoglycemic steady state of the hyper-insulinemic euglycemic hypoglycemic clamp study. Total area under the curve (AUC) for glucagon was measured during the time points of 120 minutes to 140 minutes of the clamp.
Time frame: Day 14, Day 42
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1D on MBX-2982 | Total Area Under the Curve (AUC) for Glucagon During Hypoglycemia. | 6624.6 pg*min/mL | Standard Deviation 3772.4 |
| T1D on Placebo | Total Area Under the Curve (AUC) for Glucagon During Hypoglycemia. | 6037.5 pg*min/mL | Standard Deviation 3545.9 |
| Healthy Normal Volunteers | Total Area Under the Curve (AUC) for Glucagon During Hypoglycemia. | 15923.2 pg*min/mL | Standard Deviation 5350.6 |