Effect of a Fixed Pramlintide: Insulin Dose Ratio on Postprandial Glucose in Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Single-Blind, Two-Way Crossover, Placebo-Controlled Phase I Study to Compare the 24-hour Glucose Profile and Safety of Pramlintide and Insulin, Co-Administered in a Fixed-Dose Ratio, Versus Placebo and Insulin in Patients With Type 1 Diabetes Mellitus With Inadequate Glycemic Control

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Pramlintide acetate
* Drug: Placebo
* Drug: Lispro insulin U-100
* Drug: Regular insulin U-100


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pramlintide acetate & regular insulin<br>Pramlintide will be adiministered by sc infusion at a concentration of 1000ug/mL | Drug: Pramlintide acetate<br>* Pramlintide acetate administered by a separate pump<br>* Other names: Pramlintide: SYMLIN;Drug: Lispro insulin U-100<br>* 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)<br>* Other names: Humalog insulin lispro U-100;Drug: Regular insulin U-100<br>* Use during two in-patient treatment periods (visits 4 and 5) and administered by separate pump<br>* Other names: Humulin R; U-100;|
| Placebo Comparator: Placebo and regular insulin<br>Placebo is similar sterile solution without pramlintide. | Drug: Placebo<br>* Placebo administered by separate pump<br>Drug: Lispro insulin U-100<br>* 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)<br>* Other names: Humalog insulin lispro U-100;Drug: Regular insulin U-100<br>* Use during two in-patient treatment periods (visits 4 and 5) and administered by separate pump<br>* Other names: Humulin R; U-100;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 h | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 3 hours | 
| 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). | 2 hours | 
| 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). | 2 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) | 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). | 24 h | 
| 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). | 24 h | 
| 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). | 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) | 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). | 24 h | 
| 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). | 24 h | 
| 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). | 24 h | 
| Fasting Plasma Glucose Concentration | Fasting plasma glucose concentration at 0600 hours (6:00 AM) | 12 hours after dinner meal | 
| 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). | 24 hours | 
| 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). | 24 hours | 
| 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). | 24 hours | 
| 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). | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 Diabetes Mellitus; Pramlintide