| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051153 |
| E.1.2 | Term | Diabetic gastroparesis |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To investigate the pharmacodynamic effect of single doses of GSK962040 on gastric emptying of an isotope-labeled test meal, as measured by the 13C-octanoic acid breath test in TIDM patients with gastroparesis
• To investigate safety and tolerability of single doses of GSK962040 in TIDM patients with gastroparesis
• To investigate pharmacokinetics of single doses of GSK962040 in TIDM patients with gastroparesis
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| E.2.2 | Secondary objectives of the trial |
• To investigate the pharmacodynamic effect of single doses of GSK962040 on time to first bowel movement after dose, and bowel movement parameters in TIDM patients with gastroparesis
• To investigate the PK/PD relationship for gastric emptying following single doses of GSK962040
• To explore PK/PD relationship for pancreatic polypeptide (PP), GLP-1, and ghrelin after a single dose of GSK962040
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient will be eligible for inclusion in this study only if all of the following criteria apply:
1. Controlled Type I Diabetes Mellitus (HbA1c < 10%) with onset < 30 years of age.
2. Male or female between 18 and 70 years of age, inclusive.
3. 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
• AND a minimum 3 month history of relevant symptoms for gastroparesis (e.g., chronic postprandial fullness, postprandial nausea, vomiting)
4. 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.
• 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 4 days following the last dose of study medication.
5. 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 4 days after the last dose of study medication.
6. Body weight 110 kg and BMI < 32.0 kg/m2 (inclusive).
7. Patient has never had a gastrectomy, nor major gastric surgical procedure or any evidence of bowel obstruction within the previous 12 months
8. Dosage of any concomitant medications has been stable for at least 3 weeks, except for routine adjustments in daily insulin treatments. The investigator and study team can review medication use on a case by case basis to determine if its use would compromise subject safety or interfere with study procedures or data interpretation.
9. HbA1c level is ≤ 10.0%
10. Calculated creatinine clearance >= 50 ml/min
11. 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.
12. AST, ALT, alkaline phosphatase and bilirubin =< 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
13. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
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| E.4 | Principal exclusion criteria |
A patient will not be eligible for inclusion in this study if any of the following criteria apply:
1. Patient has acute severe gastroenteritis
2. Patient has a gastric pacemaker
3. Patient is on chronic parenteral feeding
4. Patient has daily persistent severe vomiting
5. Patient has pronounced dehydration
6. Patient has had clinical diabetic ketoacidosis in last 4 weeks
7. Patient has a history of eating disorders (anorexia nervosa, binge eating, bulimia)
8. Use of medications potentially influencing upper gastrointestinal motility or appetite within one week of the study (e.g., prokinetic drugs, macrolide antibiotics (erythromycin))
9. Patient is taking opiates.
10. Use of prohibited medications listed in Section 9.2 within the restricted timeframe relative to the first dose of study medication.
11. 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.
12. 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).
13. 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).
14. 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.
15.Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
16.Pregnant females as determined by positive serum or urine hCG test (from the first urine of the day) at screening or prior to dosing.
17. Lactating or pregnant females.
18.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.
19.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.
20.A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Gastric emptying, as measured by the 13C octanoic acid breath test:
• Gastric half emptying time (t1/2b)
• Duration of the lag time (tlag)
• Gastric evacuation coefficient (GEC)
• Safety and tolerability of GSK962040:
• Adverse Events (AEs)
• Change from baseline and number of patients outside the normal range for blood pressure, heart rate, electrocardiography parameters (12-lead ECG)
• Change from baseline in clinical chemistry and hematology parameters
• Pharmacokinetic parameters of GSK962040: Cmax, Tmax, AUC(0-t), AUC(0-infinite) for single-dose, CL/F, V/F, and, if possible, half-life
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Information not present in EudraCT |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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