Clinical trial NCT01602549: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gastroparesis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-05-21
Enrollment: 58
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief 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.

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Dose-normalized Levodopa (L-DOPA) Area Under the Plasma Concentration-time Curve From Zero to 4 Hours AUC(0-4) at Baseline
timeFrame: Baseline
measure: Dose-normalized L-DOPA AUC(0-4) at Day 1 and Day 8
timeFrame: Day 1 and Day 8
measure: Dose-normalized L-DOPA Maximum Observed Concentration (Cmax) at Baseline
timeFrame: Baseline
measure: Dose-normalized L-DOPA Cmax at Day 1 and Day 8
timeFrame: Day 1 and Day 8
measure: L-DOPA Time of Occurrence of Cmax (Tmax) at Baseline, Day 1,and Day 8
timeFrame: Baseline, Day 1, and Day 8
measure: L-DOPA Terminal Phase Half-life (t1/2) at Baseline, Day 1, and Day 8
timeFrame: Baseline, Day 1, and Day 8
Secondary outcomes:
measure: Gastric Half Emptying Time (GE t1/2) at Baseline (BL), Day 1, and Day 8
timeFrame: Baseline, Day 1, and Day 8
measure: 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
measure: 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)
measure: 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)
measure: 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)
measure: 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
measure: 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
measure: Change From Baseline in Heart Rate at Day 1 and Day 8
timeFrame: Baseline, Day 1, and Day 8
measure: Number of Participants With the Indicated Electrocardiogram (ECG) Findings at Day 1 and Day 8
timeFrame: Day 1 and Day 8
measure: Change From Baseline in Albumin (ALB) and Total Protein (TP) at Day 4 and Day 8
timeFrame: Baseline, Day 4, and Day 8
measure: 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
measure: 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
measure: 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
measure: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at Day 4 and Day 8
timeFrame: Baseline, Day 4, and Day 8
measure: Change From Baseline in Hematocrit at Day 4 and Day 8
timeFrame: Baseline, Day 4, and Day 8
measure: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at Day 4 and Day 8
timeFrame: Baseline, Day 4, and Day 8
measure: Change From Baseline in Mean Corpuscle Volume (MCV) at Day 4 and Day 8
timeFrame: Baseline, Day 4, and Day 8
measure: 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
measure: Change From Baseline in Reticulocytes (RET) at Day 4 and Day 8
timeFrame: Baseline, Day 4, and Day 8
measure: 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)
measure: 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
measure: GSK962040 Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex) at Day 1
timeFrame: Day 1
measure: GSK962040 Cmax at Day1 and Day 8
timeFrame: Day 1 and Day 8
measure: GSK962040 Tmax at Day1 and Day 8
timeFrame: Day 1 and Day 8
Other outcomes:
Locations:
city: Randwick
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Bochum
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Bonn
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Jena
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Uppsala
country: Sweden
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle Upon Tyne
country: United Kingdom
facility: GSK Investigational Site
city: Norwich
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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 in Parkinson's disease. Mov Disord. 2018 Feb;33(2):329-332. doi: 10.1002/mds.27259. Epub 2017 Dec 26.