| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Investigate the ability of the motilin receptor agonist GSK962040 to improve levodopa pharmacokinetics (PK) by enhancing GE via motilin receptor agonism. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson’s disease patients with slow gastric emptying |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051153 |
| E.1.2 | Term | Diabetic gastroparesis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| 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 measure the effect of co-administration of GSK962040 on levodopa pharmacokinetic exposure in subjects with Parkinson’s disease with delayed gastric emptying |
|
| E.2.2 | Secondary objectives of the trial |
• To measure the proportion of subjects who normalize GE rate with co-administration of GSK962040
• To measure the impact of co-administration of GSK962040 on symptoms of Parkinson’s disease
• To evaluate the effect of GSK962040 co-administration on gastroparesis symptoms
• To evaluate the safety and PK profile of GSK962040 in patients with Parkinson’s disease
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of idiopathic Parkinson’s Disease (according to modified Hoehn & Yahr criteria Stages II-IV) and with suboptimal motor control on L-DOPA or L-DOPA combination therapy (i.e. wearing off, peak dose dyskinesias, delayed on or no-on
effects)
2. Subjects receiving a stable regimen of L-DOPA for at least four weeks prior to screening
3. Patient has gastroparesis at screening.
• A patient is eligible for Cohort 1 if the gastric half-time of emptying > 120.0 min as determined by 13C-oral breath test
• A patient is eligible for Cohort 2 if the gastric half-time of emptying > ULN and ≤ 120.0 min as determined by 13C-oral breath test
4. Between 40 and 80 years of age, inclusive.
5. Patient has never had a gastrectomy, nor major gastric surgical procedure or any evidence of bowel obstruction or strictures within the previous 12 months
6. Dosage of any concomitant medications has been stable for at least 4 weeks
7. A female subject is eligible to participate if she is of:
o 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 and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory].
o Child-bearing potential and is abstinent or 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 subjects must agree to use
contraception until at least 5 days post-last dose.
8. ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
9. Single or Average QTc, QTcB or QTcF< 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block. |
|
| E.4 | Principal exclusion criteria |
1. Late stage advanced subjects with incapacitating peak dose or biphasic dyskinesia on a stable L-DOPA regime.
2. Presence, or history within the previous 3 months, of significant and/or uncontrolled psychiatric, neurological (other than Parkinson’s disease), gastro-intestinal, hematological, endocrinologic, neurological (other than Parkinson’s disease),
cardiovascular disease, active malignancy (other than basal cell cancer) or other condition that would in the opinion of the investigator or medical monitor make the subject unsuitable for inclusion in this clinical study.
3. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
4. Patient has a gastric pacemaker
5. Patient is on chronic enteral (e.g., feeding tube) or parenteral feeding
6. Patient has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months)
7. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
8. Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
9. Lactating females.10. Unable to refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication until followup.
11. 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)
12. Unable to refrain from use of prohibited medications listed in Section 9 within the restricted timeframe relative to the first dose of study medication.
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 time-period. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| L-DOPA PK at screening, Days 1 and 8: dose-normalized AUC(0-4), dose-normalized Cmax, Tmax, t½, (ka) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• GE at screening, Days 1 and 8, as measured by OBT
(GE t½, GEC, GE Tlag) and
• UPDRS motor score at screening (baseline), Days 1 and 8
• Change from baseline in amount of awake time (in hours) spent “on,” “on” with troublesome dyskinesias, and “off” at screening, Days 1 through 8
• Non- motor symptoms scale at screening (baseline), Days 1 and 8
• Vital signs, clinical laboratory data and adverse events
• GSK962040 PK on Days 1 and 8: AUC, Cmax, Tmax, t½
Exploratory Endpoints
• Gastroparesis symptoms by GCSI-DD at screening, Days 1 through 8
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | No |
| 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 | Yes |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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