Type 1 Diabetes Mellitus
Conditions
Keywords
Type 1 Diabetes Mellitus; Pramlintide
Brief summary
This study is designed to investigate the clinical efficacy and safety of pramlintide co-administered as a fixed-dose ratio with basal-bolus SC insulin, delivered simultaneously via 2 separate pumps, in subjects with type 1 diabetes who are failing to achieve the desired level of glycemic control using insulin therapy.
Detailed description
Potentially eligible subjects with Type 1 diabetes mellitus who are treated with with a basal-bolus insulin regimen through multiple daily injections or insulin pump at a total daily insulin dose ≤60 U, will be eligible. Visit 1 is approximately 3-6 weeks prior to randomization. Given some variability in HbA1c and C-peptide assays, re-testing for HbA1c and C-peptide can be performed within 18 days from the initial visit. Visit 2 is approximately 2-5 weeks prior to randomization. Subjects are on lispro insulin throughout study except during Visit 4 and Visit 5, the domicile 24 hr treatment period, when they are switched to regular insulin U-100. Screen failed patients may be re-screened for inclusion in the study, as long as re-screening takes place at least 3 months after the original screening visit. If a subject is re-screened, he/she must continue to meet all inclusion/exclusion criteria. All study procedures of initial Visit 1 must be repeated at the re-screening visit.
Interventions
Pramlintide acetate administered by a separate pump
DRUGPlacebo
Placebo administered by separate pump
DRUGLispro insulin U-100
Subjects will be stabilized on a separate insulin pump and administered lispro insulin throughout the study, except during both inpatient treatment periods (Visit 4 and Visit 5)
DRUGRegular insulin U-100
Use during two in-patient treatment periods (visits 4 and 5) and administered by separate pump
Sponsors
Juvenile Diabetes Research Foundation
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent prior to any study-specific procedures * Female and/or male aged between 18 and 70 years * Must have a prior diagnosis of T1DM * Body mass index (BMI) \<30 kg/m2 * Subjects are not on current treatment with pramlintide (Symlin) and have not received pramlintide during the 6-month period prior to enrollment * Subjects should be willing to consume all of the components of the standardized meals administered during the study * Negative serum pregnancy test for female subjects of childbearing potential * Female subjects of childbearing potential must be 1 year postmenopausal, surgically sterile, or using an acceptable method of contraception for the duration of the study * Male subjects must be surgically sterile or using an acceptable method of contraception for the duration of the study
Exclusion criteria
* Recurrent severe hypoglycemia requiring assistance within 6 months before screening * A history of hypoglycemia unawareness * A confirmed diagnosis of gastroparesis * Has been treated, is currently being treated, or is expected to require or undergo treatment with the following medications: * Any oral antihyperglycemic agent or any other injectable antihyperglycemic agent that is not insulin * Drugs that directly affect GI motility (eg, anticholinergic agents such as atropine) * Drugs that slow the intestinal absorption of nutrients (eg, α-glucosidase inhibitors * A history of gastric surgery (such as gastric banding, Roux- and Y bypass) * Is expected to require or undergo treatment with acetaminophen after enrollment and at any point during the study * Has experienced diabetic ketoacidosis within the last 24 weeks * History of hospitalization within the last 6 months for glycemic control (for both hyperglycemia or hypoglycemia) * Subject has any significant disease or disorder, which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or may influence the results of the study, or the subject's ability to participate in the study * Any clinically relevant abnormal findings, which, in the opinion of the investigator, may put the subject at risk because of his/her participation in the study. * Pregnancy confirmed by a positive pregnancy test, or otherwise verified. * Breast feeding * Positive hepatitis C virus antibody (HCV Ab), hepatitis B virus surface antigen (HBsAg), hepatitis B virus core antibody (anti-Hbc), or human immunodeficiency virus 1/2 antibody (HIV-1/2 Ab) at Screening * History of, or current alcohol or drug abuse * Has donated blood within 2 months of Visit 1 (Screening) or is planning to donate blood during the study * Has had a major surgery or a blood transfusion within 2 months before Visit 1 (screening) * Participation in any clinical study with an investigational drug or new formulation of a marketed drug during the last 1 month prior to Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Pramlintide by Measurement of 24-hour Tissue Mean Weighted Glucose (MWG) Obtained With Continuous Glucose Monitoring (CGM) | 24 h | 24-hour MWG mg/dL, defined as total area under the 24-hour tissue glucose curve obtained with CGM, divided by actual time span in the 24-hour period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Dinner | 2 hours | Absolute postprandial plasma glucose AUC (AUC0-2h) was measured for the first 2 hours following dinner based on sample availability. (Sample times: 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours). |
| Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Breakfast | 2 hours | Absolute postprandial plasma glucose AUC (AUC0-2h) was measured for the first 2 hours following breakfast based on sample availability. (Sample times: 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours). |
| Efficacy of Pramlintide by Measurement of Incremental 24-hour Tissue Glucose Area Under the Plasma Concentration-time Curve (AUC) Obtained With Continuous Glucose Monitoring (CGM) | 24 h | Incremental (i.e., baseline-corrected) area under the 24-hour tissue glucose concentration curve (AUC0-24h) measured by continuous glucose monitoring (CGM) with a pre-test, non-fasting tissue glucose value as baseline. (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours). |
| Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) | 24 h | Absolute mean area under the 24-hour plasma glucose concentration curve, measured as total area under the curve (0 to 24 hours). (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours). |
| Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) | 24 hours | Incremental (i.e., baseline-corrected) mean area under the 24-hour plasma glucose concentration curve, measured as total area under the curve (0 to 24 hours). (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours). |
| Efficacy of Pramlintide Measured by Percent Time Spent in the Range of >70 mg/dL to <180 mg/dL Tissue Glucose Obtained With Continuous Glucose Monitoring (CGM) | 24 h | Percent time spent in the normoglycemic range of tissue glucose concentrations between \>70 mg/dL and \<180 mg/dL, measured by CGM. (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours). |
| Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Lunch | 3 hours | Absolute postprandial plasma glucose AUC was measured for the first 3 hours (AUC0-3h) following lunch based on sample availability. (Sample times: 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours). |
| Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC) | 24 h | Incremental (i.e., baseline-corrected) mean area under the 24-hour plasma glucagon concentration curve with a pre-test, non-fasting plasma glucagon value as baseline. (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours). |
| Fasting Plasma Glucose Concentration | 12 hours after dinner meal | Fasting plasma glucose concentration at 0600 hours (6:00 AM) |
| Pharmacokinetics of Insulin as Demonstrated by 24-hour Plasma Insulin Area Under the Plasma Concentration-time Curve (AUC) | 24 hours | Mean areas under the plasma insulin concentration curves for the 24-hour periods of pramlintide and placebo administration (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours). |
| Pharmacokinetics of Insulin as Demonstrated by 24-hour Average Plasma Insulin Concentration. | 24 hours | Mean values of the average plasma insulin concentrations over the 24-hour periods of pramlintide and placebo administration. (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours). |
| Pharmacokinetics of Insulin as Demonstrated by Maximum Plasma Insulin Concentration | 24 hours | Mean maximum plasma insulin concentrations over the 24-hour periods of pramlintide and placebo administration. (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours). |
| Pharmacokinetics of Insulin as Demonstrated by the Time to the Maximum Plasma Insulin Concentration | 24 hours | Mean time to maximum plasma insulin concentrations over the 24-hour periods of pramlintide and placebo administration. (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours). |
| Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC) | 24 h | Absolute mean area under the 24-hour plasma glucagon concentration curve, measured as total area under the curve (total AUC0-24). (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours). |
Countries
United States
Participant flow
Recruitment details
The first subject was enrolled in the study (at Visit 2) on 27 August 2015. A total of 79 subjects were screened and 34 subjects were randomized at 3 sites in the United States. One additional subject was randomized in error and was discontinued prior to receiving any study medication. The last subject completed the study on 05 August 2016.
Pre-assignment details
Eligible study subjects were males and females, aged ≥18 years and ≤70 years at the time of screening with a prior diagnosis of type 1 diabetes mellitus (T1DM) and an HbA1c value of ≥7.2% and ≤9.0% at screening.
Participants by arm
| Arm | Count |
|---|---|
| Pramlintide First, Then Placebo (Treatment Sequence A) - Safety Analysis Set | 16 |
| Placebo First, Then Pramlintide (Treatment Sequence B) - Safety Analysis Set | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 0 |
| Period 1 | Hyperglycemia | 1 | 0 |
| Period 1 | Severe non-compliance to protocol | 0 | 1 |
| Period 1 | Subject decision | 2 | 0 |
| Period 2 | Change in risk | 1 | 0 |
Baseline characteristics
| Characteristic | Pramlintide First, Then Placebo | Placebo First, Then Pramlintide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 16 Participants | 30 Participants |
| Age, Continuous | 45.1 Years STANDARD_DEVIATION 14.83 | 38.9 Years STANDARD_DEVIATION 12.68 | 42.0 Years STANDARD_DEVIATION 13.92 |
| Baseline A1c | 7.84 % STANDARD_DEVIATION 0.356 | 8.21 % STANDARD_DEVIATION 0.574 | 8.03 % STANDARD_DEVIATION 0.506 |
| Baseline C-peptide | 0.030 nmol/L STANDARD_DEVIATION 0 | 0.030 nmol/L STANDARD_DEVIATION 0.0141 | 0.030 nmol/L STANDARD_DEVIATION 0.01 |
| Baseline Fasting Glucose | 8.57 mmol/L STANDARD_DEVIATION 2.767 | 8.15 mmol/L STANDARD_DEVIATION 3.149 | 8.35 mmol/L STANDARD_DEVIATION 2.928 |
| Baseline Insulin | 38.14 U/day STANDARD_DEVIATION 12.525 | 36.58 U/day STANDARD_DEVIATION 8.92 | 37.36 U/day STANDARD_DEVIATION 10.725 |
| Body Mass Index | 25.38 kg/m^2 STANDARD_DEVIATION 2.806 | 24.52 kg/m^2 STANDARD_DEVIATION 2.341 | 24.95 kg/m^2 STANDARD_DEVIATION 2.579 |
| Current Administration of Insulin Both | 2 Participants | 0 Participants | 2 Participants |
| Current Administration of Insulin CSII | 10 Participants | 11 Participants | 21 Participants |
| Current Administration of Insulin MDI | 4 Participants | 5 Participants | 9 Participants |
| Duration of Diabetes | 27.81 Years STANDARD_DEVIATION 13.177 | 21.94 Years STANDARD_DEVIATION 10.866 | 24.88 Years STANDARD_DEVIATION 12.249 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 14 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 168.41 cm STANDARD_DEVIATION 6.966 | 167.31 cm STANDARD_DEVIATION 7.684 | 167.86 cm STANDARD_DEVIATION 7.236 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 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 | 15 Participants | 15 Participants | 30 Participants |
| Renal Status Category <30 mL/min | 0 Participants | 0 Participants | 0 Participants |
| Renal Status Category ≥30 to <60 mL/min | 2 Participants | 0 Participants | 2 Participants |
| Renal Status Category ≥60 to <90 mL/min | 8 Participants | 8 Participants | 16 Participants |
| Renal Status Category ≥90 mL/min | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Female | 13 Participants | 12 Participants | 25 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
| Weight | 72.03 kg STANDARD_DEVIATION 9.012 | 68.73 kg STANDARD_DEVIATION 8.859 | 70.38 kg STANDARD_DEVIATION 8.949 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 28 | 22 / 32 |
| serious Total, serious adverse events | 0 / 28 | 0 / 32 |
Outcome results
Primary
Efficacy of Pramlintide by Measurement of 24-hour Tissue Mean Weighted Glucose (MWG) Obtained With Continuous Glucose Monitoring (CGM)
24-hour MWG mg/dL, defined as total area under the 24-hour tissue glucose curve obtained with CGM, divided by actual time span in the 24-hour period.
Time frame: 24 h
Population: Full Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) had at least 1 efficacy assessment available from each of the 2 crossover periods and were included in the Full Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of 24-hour Tissue Mean Weighted Glucose (MWG) Obtained With Continuous Glucose Monitoring (CGM) | 173.8 mg/dL | Standard Error 8.17 |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of 24-hour Tissue Mean Weighted Glucose (MWG) Obtained With Continuous Glucose Monitoring (CGM) | 152.2 mg/dL | Standard Error 8.17 |
p-value: 0.011895% CI: [-37.8, -5.2]Linear mixed-effects model
Secondary
Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC)
Absolute mean area under the 24-hour plasma glucagon concentration curve, measured as total area under the curve (total AUC0-24). (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours).
Time frame: 24 h
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC) | 506.265 h*pmol/L |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC) | 481.633 h*pmol/L |
p-value: 0.101595% CI: [0.896, 1.011]Linear mixed-effects model
Secondary
Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC)
Absolute mean area under the 24-hour plasma glucose concentration curve, measured as total area under the curve (0 to 24 hours). (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours).
Time frame: 24 h
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) | 243.835 mmol/L*h |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) | 215.417 mmol/L*h |
p-value: 0.025895% CI: [-53.099, -3.737]Linear mixed-effects model
Secondary
Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Breakfast
Absolute postprandial plasma glucose AUC (AUC0-2h) was measured for the first 2 hours following breakfast based on sample availability. (Sample times: 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours).
Time frame: 2 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Breakfast | 23.535 mmol/L*h |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Breakfast | 19.101 mmol/L*h |
p-value: 0.005795% CI: [-7.445, -1.424]Linear mixed effects model
Secondary
Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Dinner
Absolute postprandial plasma glucose AUC (AUC0-2h) was measured for the first 2 hours following dinner based on sample availability. (Sample times: 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours).
Time frame: 2 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Dinner | 23.247 mmol/L*h |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Dinner | 17.970 mmol/L*h |
p-value: 0.009195% CI: [-9.175, -1.378]Linear mixed effects model
Secondary
Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Lunch
Absolute postprandial plasma glucose AUC was measured for the first 3 hours (AUC0-3h) following lunch based on sample availability. (Sample times: 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours).
Time frame: 3 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Lunch | 36.233 mmol/L*h |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Absolute Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) Following Lunch | 28.336 mmol/L*h |
p-value: 0.001395% CI: [-12.356, -3.438]Linear mixed effects model
Secondary
Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC)
Incremental (i.e., baseline-corrected) mean area under the 24-hour plasma glucagon concentration curve with a pre-test, non-fasting plasma glucagon value as baseline. (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours).
Time frame: 24 h
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC) | -14.954 pmol/L*h | Standard Deviation 58.9024 |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucagon Area Under the Plasma Concentration-time Curve (AUC) | -16.055 pmol/L*h | Standard Deviation 69.2684 |
Secondary
Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC)
Incremental (i.e., baseline-corrected) mean area under the 24-hour plasma glucose concentration curve, measured as total area under the curve (0 to 24 hours). (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours).
Time frame: 24 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) | 11.181 mmol/L*h | Standard Deviation 67.6648 |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Incremental 24-hour Plasma Glucose Area Under the Plasma Concentration-time Curve (AUC) | -12.753 mmol/L*h | Standard Deviation 70.0174 |
Secondary
Efficacy of Pramlintide by Measurement of Incremental 24-hour Tissue Glucose Area Under the Plasma Concentration-time Curve (AUC) Obtained With Continuous Glucose Monitoring (CGM)
Incremental (i.e., baseline-corrected) area under the 24-hour tissue glucose concentration curve (AUC0-24h) measured by continuous glucose monitoring (CGM) with a pre-test, non-fasting tissue glucose value as baseline. (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours).
Time frame: 24 h
Population: Full Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) had at least 1 efficacy assessment available from each of the 2 crossover periods and were included in the Full Analysis Set,
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide by Measurement of Incremental 24-hour Tissue Glucose Area Under the Plasma Concentration-time Curve (AUC) Obtained With Continuous Glucose Monitoring (CGM) | 26243 mg/dL*min | Standard Error 3379.8 |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide by Measurement of Incremental 24-hour Tissue Glucose Area Under the Plasma Concentration-time Curve (AUC) Obtained With Continuous Glucose Monitoring (CGM) | -2489 mg/dL*min | Standard Error 3379.8 |
p-value: <0.000195% CI: [-37326, -20139]Linear mixed-effects model
Secondary
Efficacy of Pramlintide Measured by Percent Time Spent in the Range of >70 mg/dL to <180 mg/dL Tissue Glucose Obtained With Continuous Glucose Monitoring (CGM)
Percent time spent in the normoglycemic range of tissue glucose concentrations between \>70 mg/dL and \<180 mg/dL, measured by CGM. (Sample times: 0, 30 min, 2 hours \[dinner\], 2 hours 45 min, 3 hours, 4 hours, 9 hours, 12 hours, 14 hours, 16 hours \[breakfast\], 16 hours 45 min, 17 hours, 18 hours, 20 hours \[lunch\], 20 hours 45 min, 21 hours, 23 hours, 24 hours).
Time frame: 24 h
Population: Full Analysis Set:Of the 33 correctly randomized subjects, 26 (76.5%) had at least 1 efficacy assessment available from each of the 2 crossover periods and were included in the Full Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo & Regular Insulin | Efficacy of Pramlintide Measured by Percent Time Spent in the Range of >70 mg/dL to <180 mg/dL Tissue Glucose Obtained With Continuous Glucose Monitoring (CGM) | 43.8 Percentage of time |
| Pramlintide & Regular Insulin | Efficacy of Pramlintide Measured by Percent Time Spent in the Range of >70 mg/dL to <180 mg/dL Tissue Glucose Obtained With Continuous Glucose Monitoring (CGM) | 57.2 Percentage of time |
p-value: 0.045695% CI: [1.01, 1.7]Linear mixed-effects model
Secondary
Fasting Plasma Glucose Concentration
Fasting plasma glucose concentration at 0600 hours (6:00 AM)
Time frame: 12 hours after dinner meal
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo & Regular Insulin | Fasting Plasma Glucose Concentration | 7.794 mmol/L |
| Pramlintide & Regular Insulin | Fasting Plasma Glucose Concentration | 8.459 mmol/L |
p-value: 0.37395% CI: [0.901, 1.307]Linear mixed effects model
Secondary
Pharmacokinetics of Insulin as Demonstrated by 24-hour Average Plasma Insulin Concentration.
Mean values of the average plasma insulin concentrations over the 24-hour periods of pramlintide and placebo administration. (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours).
Time frame: 24 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by 24-hour Average Plasma Insulin Concentration. | 15.855 mIU/L | Standard Deviation 7.4265 |
| Pramlintide & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by 24-hour Average Plasma Insulin Concentration. | 15.722 mIU/L | Standard Deviation 7.3649 |
Secondary
Pharmacokinetics of Insulin as Demonstrated by 24-hour Plasma Insulin Area Under the Plasma Concentration-time Curve (AUC)
Mean areas under the plasma insulin concentration curves for the 24-hour periods of pramlintide and placebo administration (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours).
Time frame: 24 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by 24-hour Plasma Insulin Area Under the Plasma Concentration-time Curve (AUC) | 380.525 mU/L*h | Standard Deviation 178.236 |
| Pramlintide & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by 24-hour Plasma Insulin Area Under the Plasma Concentration-time Curve (AUC) | 377.324 mU/L*h | Standard Deviation 176.7569 |
Secondary
Pharmacokinetics of Insulin as Demonstrated by Maximum Plasma Insulin Concentration
Mean maximum plasma insulin concentrations over the 24-hour periods of pramlintide and placebo administration. (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours).
Time frame: 24 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by Maximum Plasma Insulin Concentration | 33.144 mIU/L | Standard Deviation 17.095 |
| Pramlintide & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by Maximum Plasma Insulin Concentration | 32.838 mIU/L | Standard Deviation 16.2315 |
Secondary
Pharmacokinetics of Insulin as Demonstrated by the Time to the Maximum Plasma Insulin Concentration
Mean time to maximum plasma insulin concentrations over the 24-hour periods of pramlintide and placebo administration. (Sample times: -15 min, 0, 30 min, 1 hour 30 min, 2 hours \[dinner\], 2 hours 15 min, 2 hours 30 min, 2 hours 45 min, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 15 hours, 16 hours \[breakfast\], 16 hours 15 min, 16 hours 30 min, 16 hours 45 min, 17 hours, 18 hours, 19 hours, 20 hours \[lunch\], 24 hours).
Time frame: 24 hours
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: Of the 33 correctly randomized subjects, 26 (76.5%) subjects received at least 1 dose of pramlintide and had evaluable PD data and were, therefore, included in the PK/PD Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by the Time to the Maximum Plasma Insulin Concentration | 10.556 h | Standard Deviation 7.3466 |
| Pramlintide & Regular Insulin | Pharmacokinetics of Insulin as Demonstrated by the Time to the Maximum Plasma Insulin Concentration | 11.653 h | Standard Deviation 7.6175 |