A Study to Assess the Safety of Single Doses of GSK189075 in Subjects With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this research study is to look at concentrations of GSK189075 in blood when single doses of the drug are taken by mouth in combination with basal insulin. The clinical effects of the drug in combination with insulin on the body will also be studied. The results will help determine doses of GSK189075 can be studied in the future in the type I diabetes mellitus population.

Official Title
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A Double-blind, Randomized, Single Ascending Dose Escalation, Placebo-controlled, Crossover Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK189075 Administered to Subjects With Type 1 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: GSK189075
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male/female, 18 to 55 years old Diagnosis of type 1 diabetes mellitus for at least 6 months; and using a continuous insulin pump Willing and able to follow all study-related instructions provided by the site staff. Willing to provide signed informed consent. Exclusion Criteria: Pregnant or a nursing female. Have a past or current disease such as heart, liver, kidney, blood, brain, or other disease. Have HIV or hepatitis, or have alcohol or drugs in your system at the screening visit. Have a history of alcohol abuse or have an eating disorder Have been in another research study in the last month or have taken certain medications in the 1 week before study drug would be taken.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm a<br>GSK189075 | Drug: GSK189075<br>* investigational drug<br>|
| Placebo Comparator: Arm b<br>Placebo | Drug: placebo<br>* placebo comparator<br>* Other names: GSK189075;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All Adverse Events (AE) and Serious Adverse Events (SAE) | Data for number of participants who presented one or more adverse events (serious or non serious) was reported. An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. | Up to 6 months | 
| Number of Participants With Hypoglycemia Episodes/Events | A hypoglycemic event was defined as symptoms of hypoglycemia confirmed by a blood glucose value below normal limits [less than 3.89 millimoles per liter (mmol/L)] or 70 milligrams per deciliter (mg/dL). Symptoms of hypoglycemia without confirmed blood glucose values were reported as AEs instead of hypoglycemic events. Number of participants with hypoglycemic events were reported. | Day 1 of each treatment period | 
| Change From Baseline Vital Signs: Systolic and Diastolic Blood Pressure (SBP and DBP) | SBP and DBP were obtained during each treatment period at the indicated time points. Measurements were made with the participant lying semi-recumbent having rested in this position for at least 10 minute before the initial reading. | Day 1 of each treatment period | 
| Change From Baseline Vital Signs: Heart Rate | Heart rate was obtained during each treatment period at indicated time points. Measurements were made with the participants lying semi-recumbent having rested in this position for at least 10 minutes before the initial reading. | Day 1 of each treatment period | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Standard semi-recumbent 12-lead ECG was obtained after the participant rested for a minimum of 10 minutes (If questionable abnormality was noted on the ECG, 2 more measurements were allowed to provide an average of 3 measurements). Number of participants with abnormal ECG were reported. | Day 1 of each treatment period | 
| Number of Participants With Abnormal Clinical Chemistry Data | Clinical Chemistry data for parameters: Alanine Amino Transferase (ALT), Albumin, Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Bicarbonate, Calcium, Chloride, Creatine Kinase, Creatinine, Gamma Glutamyl Transferase (GGT), Glucose, Lactate Dehydrogenase, Magnesium, Phosphorus, Potassium, Total Bilirubin, Sodium, Total protein, triglycerides and urea/BUN was reported. Data for number of participants with abnormal clinical Chemistry data was presented. | Day 1 of each treatment period | 
| Number of Participants With Abnormal Hematology Data | Data for abnormal Hematology parameters: Basophils, Eosinophils, Hematocrit, Hemoglobin, Lymphocytes, Mean Corpuscle Hemoglobin (MCH), Mean Corpuscle Volume (MCV), Monocytes, Platelet count, Red Blood Cell (RBC), Reticulocytes, Total Neutrophils, White Blood Cell (WBC) were reported. Data for number of participants with abnormal Hematology were reported. | Day 1 of each treatment period | 
| Summary of Urine Osmolality | Urine sample was collected at screening, Day -2 (18:00h) and Day 1 (7:45h) for determination of urine osmolality which was measured in Millimole per kilogram (mmol/kg). | Day 1 (pre dose) of each treatment period | 
| Mean Creatinine Clearance | Creatinine clearance was calculated and reported in Milliliters per minute (mL/min) on Day 1 of each period for each collection interval 0-4, 4-8, 8-12, 12-16 and 16-24 hour, as well as the combined intervals of 0-12 and 0-24 hour. For urine measurements, participants were instructed to void within 30 minutes before administration of study medication. | Up to 24 hours post dose of each treatment period. | 
| Summary of Fluid Balance | On Day 1, fluid intake, urine volume and number of micturations were recorded over the intervals for each of the following dosing periods: 0-4h, 4-8h, 8-12h, 12-16h and 16-24h. From these measures, fluid balance was calculated over the 24-hour period. Fluid Balance=total fluid intake minus total urine volume. The 0-24h amounts of total Fluid Intake, total urine output, and fluid balance were calculated by adding the amounts collected during these time intervals. | Up to 24 hours post dose of each treatment period. | 
| Mean of Derived Plasma Glucose Parameters | The plasma measurements at specified time points on Day 1 were collected. Derived plasma glucose parameters were presented. | Up to 24 hours post dose of each treatment period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incremental Adjusted Weighted Means of Plasma Glucose AUC(0-4) and AUC(0-10) on Day 1 | AUC(0-10) was the plasma glucose weighted mean AUC for 0 to 10 h post-dosing and AUC(0-4) was the plasma glucose weighted mean AUC for 0 to 4 h post-dosing. Incremental Adjusted Weighted Means were presented. | Up to 24 hours post dose of each treatment period. | 
| Urinary Glucose Excretion (UGE) for Timed Subintervals up to 24 Hours Post Dose (0-24 H) | UGE was assessed for timed subintervals up to 24h post-dose. Urine samples were collected at intervals: 0-4h, 4-8h, 8-12h, 12-16h and 16-24h on study days. The 0-24h amounts excreted in urine were calculated by adding the amounts collected during these time intervals. | Up to 24 hours post dose of each treatment period | 
| Percent of Filtered Glucose in the Urine. | Filtered glucose in the urine was assessed at indicated time points and was presented as Percentage. The 0-12h and 0-24h amounts Percent of filtered glucose in the urine were calculated by adding the amounts collected during these time intervals. | Up to 24 hours post dose of each treatment period. | 
| Mean Total Urine Volume 0-24 H | Urine volume was recorded over intervals : 0-4h, 4-8h, 8-12h, 12-16h and 16- 24h on Day 1 for each dosing period. Mean total Urine volume over 24 hours was presented. | Day 1 of each treatment period | 
| Mean Creatinine Clearance 0-24 H | Urine samples for calculating creatinine clearance were obtained over the intervals: 0-4h, 4-8h, 8-12h, 12-16h and 16-24h. Mean creatinine clearance over 0-24 H was presented. | Day 1 of each treatment period | 
| Area Under the Plasma Concentration vs. Time Curve (AUC) From Time Zero (Time of Dosing) to the Last Time Point With Measurable Analyte Concentration, AUC(0-last), AUC From Time Zero to Infinite Time, AUC(0-inf) of GSK189075 Over Period | AUC(0-last) was defined as area under the plasma concentration vs. time curve from time zero (time of dosing) to the last time point with measurable analyte concentration and AUC(0-inf) was defined as area under the plasma concentration vs. time curve from time zero to infinite time. Blood samples were collected on time points: Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period. | Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | 
| Maximum Observed Plasma Concentration (Cmax) of GSK189075 Over Period | Plasma samples for pharmacokinetic analysis were drawn at indicated time points of each treatment period. Cmax was defined as maximal measured plasma concentration over the time span specified. Values were reported as Geometric Means with respective Geometric Coefficient of Variation (% CV). | Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | 
| Time to Maximum Observed Plasma Concentration (Tmax) and Terminal Half Life, (T1/2) of GSK189075 Over Period | Tmax was defined as the time to the maximum or peak concentration of a drug observed after multiple administration. T1/2 was defined as the time to when half of the total amount of a particular substance is eliminated from the body. Blood samples obtained during indicated time points. T1/2 was calculated as t1/2 = ln2/λz, with λz (the terminal elimination rate-constant) estimated from log-linear regression analysis of the terminal phase of the plasma concentration-time profile.Tmax and t1/2 values for GSK189075 were presented. | Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | 
| AUC From Time Zero to 4 Hours Post Dose, AUC(0-4) for GSK189074 Over Period | AUC(0-4) was defined as AUC from time zero to 4 hours post dose. Blood samples were collected on time points: Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period. | Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | 
| Oral Clearance (CL/F) Over Period | Oral clearance is a measure of the rate at which the drug is cleared from the body via metabolism. Blood samples were collected on time points: Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | 
| The Metabolite to Parent AUC Ratio, AUCmetabolite/AUCparent Ratio for GSK189074 Over Period | Blood samples were collected on time points: Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period to obtain the metabolite to parent AUC ratio for GSK189074 | Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | 
| The Metabolite to Parent AUC Ratio, AUCmetabolite/AUCparent Ratio for GSK279782 Over Period | Blood samples were collected on time points: Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period to obtain the metabolite to parent AUC ratio for GSK279782 | Pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 1 Diabetes mellitus, pharmacokinetics,, pharmacodynamics, Adult male and females,