Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will assess the effect of combined treatment with MK0893 plus propranolol versus placebo plus propranolol on hypoglycemia.
Interventions
DRUGMK0893
Single dose of MK0893 1000 mg (ten 100 mg tablets)
DRUGMK0893-matched Placebo
Single dose of placebo to MK0893 (ten tablets)
DRUGPropranolol Hydrochloride (HCL)
Propranolol tablets titrated up to 80 mg three times daily over a four week period. Total treatment was approximately 7 weeks.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Participant has Type 2 Diabetes (T2DM) * Participant is either: Not on an oral antihyperglycemic medication for at least 6 weeks; on a single oral antihyperglycemic medication that is not a peroxisome proliferator-activated gamma (PPAR-gamma) agonist (e.g. Avandia); OR on a combination of no more than two antihyperglycemic medications that are not PPAR-gamma) agonists * Participant has not received insulin for at least 6 months * Participant has not been treated with a PPAR-gamma agonist for at least 12 weeks * Participant has been a nonsmoker for at least 6 months * Female participants who are non-pregnant and highly unlikely to conceive due to surgical sterilization, post-menopausal status, not heterosexually active, or willing to use 2 birth control methods
Exclusion criteria
* Participant has a history of stroke, seizures, or neurological disorders * Participant cannot tolerate insulin or propranolol * Participant has a history of asthma, emphysema or chronic bronchitis * Participant is on a weight loss program that is not in the maintenance phase or has been treated with a weight loss medication within 8 weeks of screening * Participant is on or may require treatment with drugs that affect the immune system or with corticosteroids * Participant has a history of heart failure or coronary artery disease * Participant has a history of uncontrolled high blood pressure * Participant is Human Immunodeficiency (HIV), hepatitis B or hepatitis C positive * Participant has a history of Type 1 diabetes * Participant has a history of hypoglycemia unawareness documented by a blood glucose concentration \< 55 mg/dL (3.1 mol/L) without symptoms of hypoglycemia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recovery Time (Rt[65] From Insulin-induced Hypoglycemia | From the time of hypoglycemic clamp (t=0 minutes) through 270 minutes | Rt(65) defined as the time to recover from hypoglycemia (blood glucose level of 50 mg/dL) to an arterialized venous blood glucose of 65 mg/dL. At t= -60 minutes on the morning of Day 1 (Visit 6) or Day 22 (Visit 8), a hypoglycemic clamp was used via an increased insulin infusion rate to achieve blood glucose concentrations of 50 mg/dL (2.8 mmol/L) within \ 30-90 minutes. At the end of the 30-minute hypoglycemic clamp interval, insulin and glucose infusions were terminated, and the time to recover from hypoglycemia to 65 mg/dL Rt(65) was determined. Rt(65) was followed up to 270 minutes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) and Concentration Average Over 8-12 Hours (C[Ave] 8-12 hr) Post Single Dose MK0893 | From time of MK0893 administration through 24 hours post-dose | Cmax was the maximum or peak concentration of MK0893 observed after its administration. Approximate C(ave 8-12) was the MK0893 concentration average over 8-12 hours post-dose and was computed as the Area Under the Curve over 8-12 hours post-dose (AUC \[8-12\]) ÷ 4 |
| Plasma Concentration at 32 Hours (C[32hr]) Post Single Dose MK0893 | From time of MK0893 administration through estimated 32 hours post-dose | Plasma concentration of single dose MK0893 was measured from time of administration to 24 hours post-dose and extrapolated out to 32 hours post-dose using the plasma concentration vs. time curve |
| Number of Participants With An Adverse Event (AE) | From time of administration of study treatment through end of Post-Study (up to 21 days after administration of last dose of study treatment). | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. This also included any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product. |
| Number of Participants Who Discontinued Study Treatment Due To AEs | From time of first administration of study treatment to time of last administration of study treatment (up to Day 21) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. This also included any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK0893 + Propanolol Participants received a single dose of MK0893 added to a background of propanolol at either Visit 6 (Day -1) or Visit 8 (Day 21). | 12 |
| Placebo + Propanolol Participants received a single dose of MK0893-matched placebo added to a background of propanolol at either Visit 6 (Day -1) or Visit 8 (Day 21). | 10 |
| Total | 22 |
Baseline characteristics
| Characteristic | MK0893 + Propanolol | Placebo + Propanolol | Total |
|---|---|---|---|
| Age, Continuous | 51.3 years STANDARD_DEVIATION 5.66 | 48.5 years STANDARD_DEVIATION 6.88 | 50.0 years STANDARD_DEVIATION 6.26 |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 22 | 4 / 22 | 9 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 22 |
Outcome results
Primary
Recovery Time (Rt[65] From Insulin-induced Hypoglycemia
Rt(65) defined as the time to recover from hypoglycemia (blood glucose level of 50 mg/dL) to an arterialized venous blood glucose of 65 mg/dL. At t= -60 minutes on the morning of Day 1 (Visit 6) or Day 22 (Visit 8), a hypoglycemic clamp was used via an increased insulin infusion rate to achieve blood glucose concentrations of 50 mg/dL (2.8 mmol/L) within \ 30-90 minutes. At the end of the 30-minute hypoglycemic clamp interval, insulin and glucose infusions were terminated, and the time to recover from hypoglycemia to 65 mg/dL Rt(65) was determined. Rt(65) was followed up to 270 minutes
Time frame: From the time of hypoglycemic clamp (t=0 minutes) through 270 minutes
Population: 21 participants who received MK0893 + Propanolol while on study had data available, and 17 participants who received Placebo + Propanolol while on study had data available
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK0893 + Propanolol | Recovery Time (Rt[65] From Insulin-induced Hypoglycemia | 103 minutes |
| Placebo + Propanolol | Recovery Time (Rt[65] From Insulin-induced Hypoglycemia | 71 minutes |
Comparison: The p-value is for testing the null hypothesis that the difference on Rt(65) between the \[MK-0893 1g + Propranolol\] vs. \[PBO + Propranolol\] \>=60 min. If p-value \< 0.05, then the null hypothesis is rejected at the significance level of 0.05, thus supporting the primary hypothesis that the treatment difference is less than 60 minutes.p-value: 0.00595% CI: [15, 49]A linear mixed effect (LME) model
Secondary
Maximum Plasma Concentration (Cmax) and Concentration Average Over 8-12 Hours (C[Ave] 8-12 hr) Post Single Dose MK0893
Cmax was the maximum or peak concentration of MK0893 observed after its administration. Approximate C(ave 8-12) was the MK0893 concentration average over 8-12 hours post-dose and was computed as the Area Under the Curve over 8-12 hours post-dose (AUC \[8-12\]) ÷ 4
Time frame: From time of MK0893 administration through 24 hours post-dose
Population: Data from the first 15 participants who completed the study were used for the pharmacokinetic analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK0893 + Propanolol | Maximum Plasma Concentration (Cmax) and Concentration Average Over 8-12 Hours (C[Ave] 8-12 hr) Post Single Dose MK0893 | Cmax | 29.18 uM | Standard Deviation 6.51 |
| MK0893 + Propanolol | Maximum Plasma Concentration (Cmax) and Concentration Average Over 8-12 Hours (C[Ave] 8-12 hr) Post Single Dose MK0893 | C(ave) 8-12hr | 26.75 uM | Standard Deviation 6.04 |
Secondary
Number of Participants Who Discontinued Study Treatment Due To AEs
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. This also included any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product.
Time frame: From time of first administration of study treatment to time of last administration of study treatment (up to Day 21)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK0893 + Propanolol | Number of Participants Who Discontinued Study Treatment Due To AEs | 1 participants |
| Placebo + Propanolol | Number of Participants Who Discontinued Study Treatment Due To AEs | 0 participants |
| Propanolol Alone | Number of Participants Who Discontinued Study Treatment Due To AEs | 0 participants |
Secondary
Number of Participants With An Adverse Event (AE)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. This also included any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product.
Time frame: From time of administration of study treatment through end of Post-Study (up to 21 days after administration of last dose of study treatment).
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK0893 + Propanolol | Number of Participants With An Adverse Event (AE) | 10 participants |
| Placebo + Propanolol | Number of Participants With An Adverse Event (AE) | 4 participants |
| Propanolol Alone | Number of Participants With An Adverse Event (AE) | 9 participants |
Secondary
Plasma Concentration at 32 Hours (C[32hr]) Post Single Dose MK0893
Plasma concentration of single dose MK0893 was measured from time of administration to 24 hours post-dose and extrapolated out to 32 hours post-dose using the plasma concentration vs. time curve
Time frame: From time of MK0893 administration through estimated 32 hours post-dose
Population: Data from the first 15 participants who completed the study were used for the pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK0893 + Propanolol | Plasma Concentration at 32 Hours (C[32hr]) Post Single Dose MK0893 | 23.69 nM | Standard Deviation 4.86 |