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

Gastroparesis Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled, Parallel Group, Dose Ranging 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01602549
• Other study ID #: 115816
• Status: Completed
• Phase: Phase 2
• First received: May 17, 2012
• Last updated: February 5, 2015
• Start date: July 2012
• Est. completion date: May 2014

Study information

• Verified date: February 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Sweden: Medical Products AgencyAustralia: Department of Health and Ageing Therapeutic Goods AdminstrationGermany: Federal Institute for Drugs and Medical DevicesAustralia: Human Research Ethics CommitteUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Description:

MOT115816 will be conducted as a multi-center, randomized, double-blind, placebo controlled study to investigate the ability of the motilin receptor agonist GSK962040 to improve L-DOPA pharmacokinetics (PK) by enhancing gastric emptying via motilin receptor agonism. Subjects will be randomized to receive 50 mg GSK962040 or placebo in a 2:1 ratio administered orally once daily for 7-9 days. The study will consist of a screening/baseline period, a treatment period, and a 14-day post treatment safety follow-up visit. During this period participants will be asked to attend the study center for 5 visits 3 of which will last approximately 5 hours. The duration of each patient's participation in the study from screening to follow-up visit will be approximately 7-8 weeks. For three of the visits, subjects will visit the clinical unit fasted and prior to taking their first morning L-DOPA dose. Volunteers will undergo a complete physical (including cardiovascular monitoring (ECG), vital signs, blood samples, and medical history), measurement of plasma L-DOPA levels, completion of patient diary to capture the amount of awake time (in hours) spent "on" without dyskinesias, "on" with troublesome dyskinesias, "on" with non-troublesome dyskinesias, and "off" and gastric symptoms, non-motor and motor symptoms assessments (MDS-UPDRS rating scale and "finger taps") and measurement of gastric emptying rate.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 58
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator)

Related Conditions & MeSH terms

• Gastroparesis
• Parkinson Disease

Intervention

Drug:
• GSK962040 (25 mg tablet)
25 mg tablet
• Placebo
matching placebo tablet

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Randwick	New South Wales
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bochum	Nordrhein-Westfalen
Germany	GSK Investigational Site	Bonn	Nordrhein-Westfalen
Germany	GSK Investigational Site	Jena	Thueringen
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Sweden	GSK Investigational Site	Uppsala
United Kingdom	GSK Investigational Site	Cambridge
United Kingdom	GSK Investigational Site	Newcastle Upon Tyne
United Kingdom	GSK Investigational Site	Norwich

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Australia,  Germany,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the relationship between co-administration of GSK962040 doses on L-DOPA pharmacokinetic exposure in subjects with Parkinson's disease with delayed gastric emptying	L-DOPA PK at screening (baseline), Days 1 and 8: dose-normalized AUC(0-4), dose-normalized Cmax, Tmax, t½	Screening, Day 1, Day 8	No
Secondary	the effect of GSK962040 on GE in patients with Parkinson's disease	GE at screening (baseline), Days 1 and 8, as measured by the 13C octanoic acid breath test (OBT (GE t½, GEC, GE tlag))	Screening, Day 1, Day 8	No
Secondary	the impact of co-administration of GSK962040 and L-DOPA on motor and non-motor symptoms of Parkinson's disease in patients with GE t½	The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor and non-motor score	Screening, Day 1, Day 8	No
Secondary	safety and tolerability profile of co-administration of GSK962040 and L-DOPA in patients with Parkinson's disease	Amount of awake time (in hours) spent "on," "on" with troublesome dyskinesias, and "off"; Vital signs, ECG, clinical laboratory data and adverse events	Screening, Day 1, Day 8, Follow Up	No
Secondary	PK profile of GSK962040 in patients with Parkinson's disease	PK: AUC, Cmax, tmax	Day 1, Day 8	No