A Study to Assess the Effect of Repeat Doses of GSK962040 on the Pharmacokinetics of L-DOPA in Subjects With Parkinson's Disease Exhibiting Delayed Gastric Emptying

• Status: Completed
• Trial end date: 2014-05-01
• Target enrollment: 0
• Participant gender: All

Summary

Gastric emptying is the end-result of a complex and carefully regulated series of events which follow the ingestion of a meal, each of which is dependent on the other and subject to neurohormonal control. Motilin is an endogenous peptide, produced mainly in the duodenum, whose physiological action is mediated by motilin receptors located on enteric neurons, peripheral terminals of the vagus, and on the smooth muscle of the gut. Motilin and non-peptide agonists at motilin receptors increases the gastric emptying rate and therefore provide a potential approach to the treatment of a range of clinical conditions in which delayed gastric emptying is thought to be part of the physiopathology and may be contributory to symptoms. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurones. It affects 1.5% of the global population over 65 years of age. Cardinal symptoms comprise bradykinesia, rigidity, resting tremors and postural instability. Gastrointestinal dysfunction, including gastroparesis, is a frequent feature of PD affecting approximately 90% of patients, and is caused by autonomic dysfunction as well as an adverse effect of antiparkinsonian drug therapy. The therapeutic mainstay for PD treatment is the neutral amino acid L-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine prodrug, as it provides the most rapid and effective symptomatic control of motor impairment in PD. The primary determinant of L-DOPA bioavailability is gastric emptying (GE); delays in GE slow delivery of L-DOPA to its proximal small intestinal absorption sites, increasing the extent of presystemic metabolism, and leading to slowed and diminished absorption.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: GlaxoSmithKline

Criteria

Inclusion Criteria:

• 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)

• Subjects receiving a stable regimen of L-DOPA for at least four weeks prior to screening

• Patient has gastric half-time of emptying > or = 70 min as determined by 13C oral breath test

• Between 40 and 80 years of age, 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 4 weeks

• A female subject 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 and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]. 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.

• ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

• Single or Average QTc, QTcB or QTcF< 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.

Exclusion Criteria:

• Late stage advanced subjects with incapacitating peak dose or biphasic dyskinesia ona stable L-DOPA regime.

• 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.

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

• Patient has a gastric pacemaker

• Patient is on chronic enteral (e.g., feeding tube) or parenteral feeding

• Patient has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months)

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

• Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.

• Lactating females.

• 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.

• 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)

• Unable to refrain from use of prohibited medications listed in Section 9 within the restricted timeframe relative to the first dose of study medication.

• 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.