Dose Response of 28 Days of Dosing of GSK962040 in Type I and II Diabetic Male and Female Subjects With Gastroparesis

Study Overview
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Brief Summary
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GSK962040 is a novel small molecule motilin agonist. The Phase I studies (MOT107043 and MOT109681) demonstrated that single doses of GSK962040 up to 150 mg and repeat dosing of up to 125 mg/day for 14 days were well tolerated with adverse events not occurring in greater prevalence than placebo, and no significant abnormal vital sign, ECG, or clinical laboratory findings. Pharmacokinetic parameters were linear and approximately dose proportional over the range of doses administered. Single doses of 50 mg - 150 mg GSK962040 significantly increased the rate of gastric emptying up to 40% as measured by the 13C octanoic acid stable isotope breath test. A similar effect of 50 mg and 125 mg on gastric emptying was observed throughout repeated dosing to healthy volunteers for 14-days. The aims of the present investigation (MOT114479) are to assess the pharmacodynamic effects (gastric emptying and symptoms), safety, tolerability, and pharmacokinetics of GSK962040 after 28 days of once-daily dosing in Type I and Type II diabetic subjects with gastroparesis. An additional aim is to characterize the dose/exposure - pharmacodynamic effect relationship.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Multicenter Phase II Study to Evaluate the Safety and Efficacy and Dose Response of 28 Days of Once-Daily Dosing of the Oral Motilin Receptor Agonist GSK962040, in Type I and II Diabetic Male and Female Subjects With Gastroparesis

Conditions
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Gastroparesis

Intervention / Treatment
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* Drug: GSK962040 (5 mg tablet)
* Drug: GSK962040 (25 mg tablet)
* Drug: GSK962040 (125 mg tablet)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type I or II Diabetes Mellitus (HbA1C < 10%) Male or female between 18 and 80 years of age, inclusive. Patient has gastroparesis at screening (gastric half-time of emptying > upper limit of normal as determined by 13C-oral breath test) Patient must have a > or = 3 month history of relevant symptoms of gastroparesis (e.g., chronic post-prandial fullness, early satiety, postprandial nausea), patients will have a mean of the daily scores over a minimum of 7 days indicating > or = mild (2) and < or = severe (4) post-prandial fullness assessed using the GCSI-DD during the screening period prior to randomization. A female patient is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL, or a value consistent with the local laboratory standard value, is confirmatory. OR Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female patients must agree to use contraception for at least 5 days following the last dose of study medication. Male patients must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication through at least 5 days after the last dose of study medication. BMI >18 and < or = 35.0 kg/m2 (inclusive). Patient has never had a gastrectomy, nor major gastric surgical procedure or any evidence of bowel obstruction or strictures within the previous 12 months Dosage of any concomitant medications has been stable for at least 3 weeks, except for routine adjustments in daily insulin treatments. Estimated (or measured) glomerular filtration rate > or = 30 mL/min. QTcB or QTcF < 450 msec or QTc < 480 msec in patients with Bundle Branch Block based on single or average QTc value of triplicate values obtained over a brief recording period. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. AST and ALT < 2xULN; alkaline phosphatase and bilirubin < or = 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Exclusion Criteria: Patient has acute severe gastroenteritis Patient has a gastric pacemaker Patient is on chronic parenteral feeding Patient has pronounced dehydration Recent (last 6 weeks) history of poor control of diabetes e.g. hypoglycaemia requiring medical intervention, diabetic ketoacidosis, admission for control diabetes or complications of diabetes Patient has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months) Patient has a history of eating disorders (anorexia nervosa, binge eating, bulimia) Use of medications potentially influencing upper gastrointestinal motility or appetite within one week of the study (e.g., prokinetic drugs, macrolide antibiotics (erythromycin), GLP-1 mimetics) Regular opiate use Use of prohibited medications listed in Section 9.2 within the restricted timeframe relative to the first dose of study medication. History or presence of clinically significant gastro-intestinal, hepatic or renal disease or other condition that would in the opinion of the investigator or medical monitor make the subject unsuitable for inclusion in this clinical study. The patient has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day time-period. Pregnant females as determined by positive serum or urine hCG test (from the first urine of the day) at screening or prior to dosing. Lactating females. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK962040 (10 mg)<br>GSK962040 10 mg | Drug: GSK962040 (5 mg tablet)<br>* 5 mg tablet<br>|
| Experimental: GSK962040 (50 mg)<br>GSK962040 50 mg | Drug: GSK962040 (25 mg tablet)<br>* 25 mg tablet<br>|
| Experimental: GSK962040 (125 mg)<br>GSK962040 125 mg | Drug: GSK962040 (125 mg tablet)<br>* 125 mg tablet<br>|
| Experimental: Placebo<br>Placebo | Drug: GSK962040 (5 mg tablet)<br>* 5 mg tablet<br>Drug: GSK962040 (25 mg tablet)<br>* 25 mg tablet<br>Drug: GSK962040 (125 mg tablet)<br>* 125 mg tablet<br>Drug: Placebo<br>* matching placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastric Half Emptying Time (GEt1/2) | Gastric half emptying time is the time taken for half the contents of the stomach to empty. Gastric emptying was measured using the 13C-oral breath test, which is a tracer method that utilizes 13C, a non-radioactive isotope. Basal breath samples were obtained after an overnight fast or otherwise after 4 hours of fasting following a light meal. On Day 1 and Day 28, participants were then dosed with GSK962040 and additional breath test samples were taken prior to administration of a 13C-labelled test meal. The test meal was consumed approximately 80 minutes(min) later. After consumption of the test meal, breath samples were collected at pre-specified time points over an approximately 4 hour period following the test meal. For the duration of the breath test, no food or drink were allowed. The 13C breath content was determined by isotope ratio mass spectrometry. GE t1/2 was determined by using the cumulative percentage of the administered dose of 13C excreted in breath over 4 hours. | Screening2/Baseline (Day -30 to -1) , Day 1, and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With On-treatment Adverse Events (AES) and Serious Adverse Events(SAEs) | An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. Data for on-treatment adverse events is reported. | Up to follow-up (5-10 days post last dose) | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure(DBP) at Specified Time Points in Semi-supine Position | Blood pressure measurements were taken at pre-dose and at 120 min (completion of meal) on Day 1 and Day 28. The Baseline value was Day 1 Pre-Dose values. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline, Day 1, and Day 8 | 
| Change From Baseline in Heart Rate at Specified Time Points in Semi-supine Position | Heart rate measurements were taken at pre-dose and 120 min (completion of meal) on Day 1 and Day 28. The Baseline value was Day 1 Pre-Dose values . Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline, Day 1, and Day 8 | 
| Change From Baseline in Electrocardiography Parameters (12-lead ECG) | ECG measurements were taken at pre-dose and 0 min (completion of meal) on Day 1 and Day 28. The Baseline value was the Day 1 pre-dose value. ECG parameters included PR interval, QRS duration, QT interval, QTcB, QTcF and RR interval. | Baseline, Day 1 and Day 28 | 
| Number of Participants Outside the Normal Range for SBP and DBP | Blood pressure measurements were taken at pre-dose and at 120 min (completion of meal) on Day 1 and Day 28. The clinical concern range (CCR) for SBP was greater than (<) 85 and less than (>) 160 and for DBP the range was <45 and >100. Data for semi-supine position has been presented. Baseline was Screening2/Baseline values. | Screening2/Baseline (Day -30 to -1), Day 1 and 28 | 
| Number of Participants Outside the Normal Range for Heart Rate | Heart rate measurements were taken at pre-dose and at 120 min (completion of meal) on Day 1 and Day 28. The CCR for heart rate was Increase or decrease by less than or equal to (>=) 15 and >= 30. Data for semi-supine position has been presented. Baseline was Screening2/Baseline values. | Screening2/Baseline (Day -30 to -1), Day 1 and 28 | 
| Number of Participants Outside the Normal Range for 12-lead ECG | ECG measurements were taken at pre-dose and 0 min (completion of meal) on Day 1 and Day 28. The CCR for ECG parameters were: PR interval (<110 and >220), QRS interval (<75 and >110), Absolute QTc interval (>450 to =< 480) respectively. Baseline was the pre-dose reading for Day 1. Data for abnormal- clinically significant (ACS) and abnormal- not clinically significant (ANCS) has been presented. | Baseline (Day 1 pre-dose), Day 1, Day 14 and Day 28 | 
| Mean Change From Baseline in Clinical Chemistry: Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Gamma Glutamyl Transferase, Creatine Kinase, Lactate Dehydrogenase | Alkaline phosphatase, alanine amino transferase, aspartate amino transferase, gamma glutamyl transferase, creatine kinase, lactate dehydrogenase measurements were taken at Baseline (Day 1 pre-dose), Day 5, 10, 14, 21 and 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose), Day 5, 10, 14, 21 and 28 | 
| Mean Change From Baseline in Clinical Chemistry: Direct Bilirubin, Total Bilirubin, Creatinine, Uric Acid | Direct Bilirubin, Total Bilirubin, Creatinine, Uric acid measurements were taken at Baseline (Day 1 pre-dose), Day 5, 10, 14, 21 and 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose), Day 5, 10, 14, 21 and 28 | 
| Mean Change From Baseline in Clinical Chemistry : Albumin, Total Protein | Albumin, Total Protein measurements were taken at Baseline (Day 1 pre-dose), and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Mean Change From Baseline in Clinical Chemistry : Calcium, Chloride, Glucose, Potassium, Sodium, Urea/BUN, Carbon Dioxide Content/Bicarbonate | Calcium, Chloride, Glucose, Potassium, Sodium, Urea/BUN, Carbon dioxide content/Bicarbonate measurements were taken at Baseline (Day 1 pre-dose) and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Mean Change From Baseline in Hematology Parameters : Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Total ANC - Total Absolute Neutrophil Count), Platelet Count, White Blood Cell Count | Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Total ANC - Total Absolute Neutrophil Count), Platelet count, White Blood cell count measurements were taken at Baseline (Day 1 pre-dose) and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Mean Change From Baseline in Hematology Parameters : Hematocrit | Hematocrit measurements were taken at Baseline (Day 1 pre-dose) and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Mean Change From Baseline in Hematology Parameters : Mean Corpuscle Hemoglobin | Mean Corpuscle Hemoglobin measurements were taken at Baseline (Day 1 pre-dose) and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Mean Change From Baseline in Hematology Parameters : Hemoglobin, Mean Corpuscle Hemoglobin Concentration | Hemoglobin, Mean Corpuscle Hemoglobin concentration measurements were taken at Baseline (Day 1 pre-dose) and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Mean Change From Baseline in Hematology Parameters : Mean Corpuscle Volume | Mean Corpuscle Volume measurements were taken at Baseline (Day 1 pre-dose) and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Mean Change From Baseline in Hematology Parameters : Red Blood Cell Count, Reticulocytes | Red Blood Cell count, Reticulocytes measurements were taken at Baseline (Day 1 pre-dose) and Day 28. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline (Day 1 pre-dose) and Day 28 | 
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration AUC(0-t) at Specified Time Points | AUC(0-t) was derived from GSK962040 plasma concentration-time data. AUC was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.Only participants who received GSK962040 drug were analyzed. | Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28 | 
| Maximum Observed Concentration (Cmax) at Specified Time Points | Cmax is defined as the maximum observed drug concentration after administration. Cmax was determined directly from the raw concentration-time data. Samples were collected at the following times: Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose. | Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28 | 
| Time of Occurrence of Cmax (Tmax) at Specified Time Points | Tmax is defined as the time to reach the observed maximum concentration. Samples were collected at the following times: Tmax was determined directly from the raw concentration-time data. Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose. | Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28 | 
| Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ct) at Specified Time Points | Analysis of pre-dose (trough) concentration at the end of the dosing interval (Ct) was planned to be performed from the samples collected at Pre -dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28. | Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28 | 
| Apparent Clearance Following Oral Dosing (CL/F) at Specified Time Points | CL/F was calculated as dose/AUC. The parameter was planned to be analyzed from samples collected at Pre -dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28, however the data for this outcome measure was not collected. | Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28 | 
| Apparent Volume of Distribution (V/F) at Specified Time Points | The apparent volume of distribution V/F = CL/F × MRT, where MRT is the mean residence time. The parameter was planned to be analyzed using samples collected at Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28, however, the data for this outcome measure was not collected. | Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28 | 
| Apparent Terminal Elimination Half-life (t1/2) at Specified Time Points | This outcome measure was not analyzed in results. | The parameter was planned to be analyzed using samples collected at Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28, however, the data for this outcome measure was not collected. | 
| Time to First Bowel Movement After First Dose | The time to first bowel movement was calculated as the time of the first bowel movement after the first dose in hours (floored) for each participant. If a participant had fewer than 5 days worth of data then the daily mean for that week was set to missing for the following two parameters: Bowel Movement Count and Stool Consistency. Seventeen participants who entered their time of first instance of bowel movement before taking first dose were excluded from the summary statistics of time to first bowel movement. | Up to Day 28 | 
| Daily Bowel Movement Frequency | Daily bowel movement frequency analyzed number of times passed stools in 24 hours of duration. Following dosing with study medication, stool monitoring was performed up to Day 28. Seventeen participants who entered their time of first instance of bowel movement before taking first dose were excluded from the summary statistics. | Up to Week 4 (Day 28) | 
| Daily Average Stool Consistency | Stool consistency was determined on a scale of 1 to 5 (1 = Very hard, 2 = Hard, 3 = Formed, 4 = Loose, 5 = Watery). Following dosing with study medication, stool monitoring was performed up to Day 28. Participants who entered their time of first instance of bowel movement before taking first dose were excluded from the summary statistics. | Up to Week 4 (Day 28) | 
| Change From Baseline in Upper Gastrointestinal (GI) Symptoms as Assessed by Total Gastrointestinal Cardinal Symptom Index - Daily Diary (GCSI-DD) | GCSI-DD was measured on a 6-point scale. The Total GCSI-DD score was the mean of the following three subscales: Nausea/Vomiting Subscale = mean (nausea, retching, vomiting), Fullness/Early Satiety Subscale = mean (feeling excessively full after meals, not able to finish a normal-sized meal, stomach fullness, loss of appetite), Bloating Subscale = mean (bloating, stomach or belly visibly larger). Each subscale was scored on a severity scale of 0 (none) to 5 (very severe), with lower scores representing less symptom severity. The change from Baseline to each study week in average score was derived and if it improved by 1 point or more, that participant was defined as responder for that symptom and on that particular week. Baseline was Screening2/Baseline values (Day -30 to -1). Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Up to 14 days post last dose (Day 28) | 
| Change From Baseline in Whole Bowel Transit Time, 100 % Gastric Emptying Time (Truncated at 240 Minutes), Small Bowel Transit Time, Colonic Transit Time as Determined by Wireless Motility Capsule (WMC) | WMC is an ingestible telemetric capsule which measures pH, pressure and temperature to assess total gastric emptying time, small and large bowel transit time, colonic transit time, and whole gut transit time. The WMC was ingested immediately following the standard test meal for the oral breath test. Data was collected on a data logger, which was worn on a belt clip. The WMC passed naturally in the participant's stools between 2 and 5 days after ingestion. The parameters Whole bowel transit time, 100 % gastric emptying time (truncated at 240 minutes), small bowel transit time, colonic transit time were analyzed. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value. | Baseline(Screening i.e., Day -30 to -1), Day 1 and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tolerability, pharmacokinetics, 13 C oral breath test, Type I and II Diabetes mellitus, gastroparesis, gut motility, phase II, pharmacodynamics, repeat dose, gastric emptying, symptoms, GSK962040