The Effect of Single Doses of the Motilin Receptor Agonist GSK962040 in Type I Diabetic Patients With Gastroparesis

Inclusion criteria

• Controlled Type 1 Diabetes Mellitus (glucose < 250 mg/dL) with onset < 30 years of age.
• Male or female between 18 and 70 years of age, inclusive.
• Patient has documented diagnosis of moderate to severe gastroparesis (> 30% at 2 h as determined by scintigraphy; or t1/2b > 109 min as determined by 13C-octanoic acid breath test). All of the following apply:
• Confirmed delayed gastric emptying (properly conducted gastric emptying assessments within last 6 months acceptable) AND a minimum 3 month history of relevant symptoms for gastroparesis (e.g., chronic postprandial fullness, postprandial nausea, vomiting)
• A female patient is eligible to participate if she is of:
• Non-childbearing potential
• Child-bearing potential and agrees to use contraception for at least 4 days following the last dose of study medication.
• Male patients must agree to use contraception from the time of the first dose of study medication through at least 4 days after the last dose of study medication.
• Body weight ≤110 kg and BMI < 32.0 kg/m2 (inclusive).
• Patient has never had a gastrectomy, nor major gastric surgical procedure or any evidence of bowel obstruction 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
• HbA1c level is ≤ 10.0%
• Calculated creatinine clearance > or equal to 50 ml/min
• QTcB or QTcF < 450 msec or QTc<480msec in patients with Bundle Branch Block based on single or average QTc value of triplicate values obtained over a brief recording period.
• AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion criteria

• Patient has acute severe gastroenteritis
• Patient has a gastric pacemaker
• Patient is on chronic parenteral feeding
• Patient has daily persistent severe vomiting
• Patient has pronounced dehydration
• Patient has had clinical diabetic ketoacidosis in last 4 weeks
• 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))
• Patient is taking opiates.
• 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 known to interfere with the absorption, distribution, metabolism or excretion of drugs.
• Presence of thyroid dysfunction (NOTE: patients with abnormal TSH at screening/baseline are not eligible. Patients with a history of hypothyroidism on a stable dose of thyroid replacement therapy are eligible to participate in the 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 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 or pregnant females.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Patients deemed unable to comply with the procedures outlined in the protocol may be excluded at the Investigator's discretion.
• For male volunteers: An unwillingness of the male patient to comply with the contraception requirements listed in Section 8.1, from the time of the first dose of study medication until at least 4 days following administration of the last dose of study medication.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.