Last updated: 11/07/2018 09:53:26
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
EudraCT ID
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
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
Trial description: 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.
Primary purpose:
Other
Trial design:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
Dose-normalized levodopa (L-DOPA) area under the plasma concentration-time curve from zero to 4 hours AUC(0-4) at Baseline
Timeframe: Baseline
Dose-normalized L-DOPA AUC(0-4) at Day 1 and Day 8
Timeframe: Day 1 and Day 8
Dose-normalized L-DOPA maximum observed concentration (Cmax) at Baseline
Timeframe: Baseline
Dose-normalized L-DOPA Cmax at Day 1 and Day 8
Timeframe: Day 1 and Day 8
L-DOPA time of occurrence of Cmax (Tmax) at Baseline, Day 1,and Day 8
Timeframe: Baseline, Day 1, and Day 8
L-DOPA terminal phase half-life (t1/2) at Baseline, Day 1, and Day 8
Timeframe: Baseline, Day 1, and Day 8
Secondary outcomes:
Gastric half emptying time (GE t1/2) at Baseline (BL), Day 1, and Day 8
Timeframe: Baseline, Day 1, and Day 8
Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores at Baseline, Day 1, and Day 8 (pre-levodopa dose)
Timeframe: Baseline, Day 1, and Day 8 at pre-levodopa dose
Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores at Baseline, Day 1, and Day 8 (pre-dose; 120, 180, and 240 minutes post-dose)
Timeframe: Baseline, Day 1, and Day 8 at pre-dose and 120, 180, and 240 minutes (min) post-dose (PD); Follow-up visit (up to Day 25)
Period mean amount of hours spent “ON,” “ON” without dyskinesia, "ON" with non-troublesome dyskinesia, "ON" with troublesome dyskinesia, and “OFF” at Baseline and during the treatment period (Days 1-8), Week 1 of Follow-up, and Week 2 of Follow-up
Timeframe: Baseline, Days 1-8, Week 1 of Follow-up (Days 6 and 7 of Follow-up; up to Day 16), and Week 2 of Follow-up (Days 13 and 14 of Follow-up; up to Day 23)
Number of times a participant could alternatively tap two counter keys 30 centimeters apart in 1 minute (min) at Baseline, Day1, Day 8, and Follow-up
Timeframe: Baseline, Day 1, and Day 8 at pre-dose and 0, 30, 60, 90, 120, 180, and 240 minutes post-dose; Follow-up visit (up to Day 25)
Total daily L-DOPA equivalent dose at Baseline and on Days 1, 2, 3, 4, 5, 6, 7, 8, and 9
Timeframe: Baseline and Days 1, 2, 3, 4, 5, 6, 7, 8, and 9
Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1 and Day 8
Timeframe: Baseline, Day 1, and Day 8
Change from Baseline in heart rate at Day 1 and Day 8
Timeframe: Baseline, Day 1, and Day 8
Number of participants with the indicated electrocardiogram (ECG) findings at Day 1 and Day 8
Timeframe: Day 1 and Day 8
Change from Baseline in albumin (ALB) and total protein (TP) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in calcium, chloride, carbon dioxide content (CO2)/bicarbonate (BC), glucose, potassium, sodium, urea/blood urea nitrogen (BUN), and uric acid (UA) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, total absolute neutrophil count (ANC), and platelet count (PC) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in hematocrit at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in mean corpuscle hemoglobin (MCH) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in mean corpuscle volume (MCV) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in red blood cell count (RBC) and white blood cell count (WBC) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Change from Baseline in reticulocytes (RET) at Day 4 and Day 8
Timeframe: Baseline, Day 4, and Day 8
Number of participants with any adverse event (AE) or serious adverse event (SAE)
Timeframe: From the start of study medication until Follow-up (up to Day 25)
GSK962040 area under the plasma concentration-time curve from zero to 5.5 hours (AUC[0-5.5] and area under the plasma concentration-time curve from zero to infinity (AUC[0-inf]) at Days 1 and 8
Timeframe: Day 1 and Day 8
GSK962040 percentage of AUC(0-inf) obtained by extrapolation (%AUCex) at Day 1
Timeframe: Day 1
GSK962040 Cmax at Day1 and Day 8
Timeframe: Day 1 and Day 8
GSK962040 tmax at Day1 and Day 8
Timeframe: Day 1 and Day 8
Interventions:
Enrollment:
58
Primary completion date:
2014-01-05
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Marrinan SL, Otiker T, Vasist LS, Gibson RA, Sarai BK, Barton ME, Richards DB, Hellstrom PM, Nyholm D, Dukes GE, Burn DJ. A randomized, double-blind, placebo-controlled trial of camicinal as a gastroprokinetic in Parkinson’s disease. Mov Disord. 2018;33(2):329-332.
Medical condition
Gastroparesis
Product
camicinal
Collaborators
Not applicable
Study date(s)
July 2012 to May 2014
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
40 - 80 years
Accepts healthy volunteers
No
- 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
- 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.
Inclusion and exclusion 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.
Trial location(s)
Location
GSK Investigational Site
Randwick, New South Wales, Australia, 2031
Status
Study Complete
Location
GSK Investigational Site
Bonn, Nordrhein-Westfalen, Germany, 53105
Status
Study Complete
Location
GSK Investigational Site
Ulm, Baden-Wuerttemberg, Germany, 89081
Status
Study Complete
Location
GSK Investigational Site
Koeln, Nordrhein-Westfalen, Germany, 50937
Status
Study Complete
Showing 1 - 6 of 11 Results
Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
Protocol
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2014-01-05
Actual study completion date
2014-01-05
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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