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

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

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.

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